EP0358118A1 - Phenylamides - process for their preparation as well as a drug containing those compounds - Google Patents

Phenylamides - process for their preparation as well as a drug containing those compounds Download PDF

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Publication number
EP0358118A1
EP0358118A1 EP89116153A EP89116153A EP0358118A1 EP 0358118 A1 EP0358118 A1 EP 0358118A1 EP 89116153 A EP89116153 A EP 89116153A EP 89116153 A EP89116153 A EP 89116153A EP 0358118 A1 EP0358118 A1 EP 0358118A1
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Prior art keywords
group
alkyl
dimethylethyl
benzamide
amino
Prior art date
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EP89116153A
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German (de)
French (fr)
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EP0358118B1 (en
Inventor
Wolfgang Dr. Rer. Nat. Von Der Saal
Alfred Dr. Rer. Nat. Mertens
Harald Dr. Rer. Nat. Zilch
Erwin Dr. Med. Boehm
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Roche Diagnostics GmbH
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Roche Diagnostics GmbH
Boehringer Mannheim GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/12—Antihypertensives
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    • C07C233/00—Carboxylic acid amides
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    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
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    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/42—Y being a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to medicaments containing phenylamides of the general formula I, in the R1, R2, R3, may be the same or different and each have a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, halogen, nitro, amino, formyl, hydroxy, Mercapto, cyano group, one by an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, benzyl, pyridinyl, alkylsulfonyl, trifluoromethylsulfonyl, alkylcarbonyl, cyanoalkyl, hydroxyalkyl, dialkylaminoalkyl, Aminocarbonylalkyl, dialkylaminocarbonylalkyl, N-cycloalkyl-N-alkylaminocarbonylalkyl, carboxyal
  • Drugs containing these compounds have valuable pharmacological properties, in particular they have an inhibitory effect on erythrocyte aggregation and can thus be used for the treatment of diseases in which erythrocyte aggregation plays an important role in pathogenesis, such as e.g. peripheral, coronary and cerebral circulatory disorders, shock conditions, etc.
  • the compounds also influence platelet function, increase heart strength and lower blood pressure.
  • patent applications CH 609,558 and US 398522 (Sept. 18, 1973, L. Givaudan et Cie.) Describe the antibacterial activity of compounds in which R4, R5, R6 is a methyl group, B is a carbonyl group, A is an imino group -NH -, X represents a valence line and one of the substituents R1, R2, R3 in the meta position of the phenyl ring represents the trifluoromethyl group and the other two represent a hydrogen or halogen atom or a trifluoromethyl group, especially the compounds 4- (1,1-dimethyl-ethyl) -N- [3-trifluoromethyl) phenyl] benzamide and of N- [4-chloro-3-trifluoromethyl) phenyl) -4- (1,1-dimethylethyl) benzamide.
  • Patent application US 4160097 (Westwood Pharmaceuticals, July 3, 1979) describes the anti-inflammatory effect of 4- (1,1-dimethylethyl) -N- [2- (1H-imidazol-1-yl) phenyl] benzamide.
  • alkyl "alkenyl” or “alkynyl” parts of the groups mentioned for the substituents R1, R2, R3, R5 and R6 can contain 1-6 or 2-6 carbon atoms and be straight-chain or branched. Straight-chain derivatives with 1-4 or 2-4 carbon atoms are preferred.
  • it means the methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl and hexyl group, the methoxy, ethoxy, n Propyloxy, i-propyloxy, allyloxy, i-butenyloxy, propinyloxy, n-butyloxy, tert-butyloxy, i-butyloxy, n-pentyloxy, n-hexyloxy, methylsulfonyloxy, ethylsulfonyloxy -, n-Propylsulfonyloxy-, i-Propylsulfonyloxy-, Methylcarbonyloxy-, Ethylcarbonyloxy-, Propylcarbonyloxy-, Cyanethyloxy-, Carboxyethoxy-, E
  • R1, R2, R3 which are preferred are the phenyl group, in the event that R1, R2, R3 represents a substituted hydroxy group, the phenyloxy, pyridinyloxy and the benzyloxy group; further halogen atoms such as fluorine, chlorine or bromine, the nitro, amino, formyl, hydroxy, mercapto, cyano, formylamino, carboxy, piperidinosulfonyl, morpholinosulfonyl and the thiomorpholinosulfonyl group and the hydrogen atom.
  • R1, R2, R3 represents a substituted hydroxy group, the phenyloxy, pyridinyloxy and the benzyloxy group
  • further halogen atoms such as fluorine, chlorine or bromine, the nitro, amino, formyl, hydroxy, mercapto, cyano, formylamino, carboxy, piperidinosulfonyl, morpholinos
  • R1 is the hydrogen atom, the methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, fluorine, chlorine, bromine, nitro, amino, hydroxy, Mercapto, formyl, cyano, formylamino, carboxy, C1-C4 alkyl, C1-C4 alkoxy, allyloxy, i-butenyloxy, propargyloxy, cyanomethyloxy, ethoxycarbonylmethoxy, aminocarbonyl, methoxycarbonyl , Ethoxycarbonyl-, C1-C3-dialkylamino-, C1-C3-alkylmercapto-, C1-C3-alkylsulfinyl, C1-C3-alkylsulfonyl-, C1-C3-alkylsulfonyloxy-, the phenyl, phenyl, phenyl
  • Preferred monosubstituted phenyls are fluorine, chlorine, bromine, hydroxy, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyloxy, propargyloxy, cyanomethoxy, methoxycarbonylmethyloxy -, Nitro, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, C1-C3-dialkylamino, C1-C3-alkylmercapto-, C1-C3-alkylsulfinyl, C1-C3-alkylsulfonyl-, C1-C3-alkylsulfonyloxy-, trifluoromethylsulfonyl -
  • the substituent can be in the 2-, 3- or 4-position.
  • Preferred disubstituted phenyls contain, as substituents, C1-C4-alkyl, chlorine, hydroxy, C1-C4-alkoxy, methylenedioxy, C1-C4-alkylsulfonyloxy-, trifluoromethylsulfonyloxy-, C1-C4-alkythio-, C1-C4- Alkylsulfinyl, C1-C4-alkylsulfonyl, C1-C4-alkylsulfonylamino, trifluoromethylsulfonylamino, cyanomethyloxy or methoxycarbonylmethyloxy group, where the groups can be identical or different and are in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-position can stand.
  • Preferred trisubstituted phenyls have as substituents C1-C4-alkyl, C1-C4-alkenyl, C1-C4-alkenyloxy and chlorine groups, where the radicals can be the same or different and in 2,3,4-, 2,3 , 5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-position can stand.
  • X denotes an alkylene group, it means the methylene, ethylene, propylene and the butylene group.
  • the vinylene group is particularly suitable as the alkenylene group.
  • R5 or R6 in the general formula I denotes an alkyl group, this means straight-chain or branched alkyl chains with 1-6 C atoms.
  • the methyl, ethyl, propyl and butyl groups are particularly preferred.
  • R6 denotes a cycloalkyl group, the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups are preferred.
  • R1 is in the ortho position of the phenyl ring, in the sense of the present invention there is in particular for R1 a hydrogen or chlorine atom, a C1-C4 alkoxy such as Methoxy, and the nitro group in question.
  • R2 represents the substituent in the meta position, this is in particular a hydrogen or chlorine atom, or a C1-C4 alkoxy such as methoxy group.
  • R3 is in the para position of the phenyl ring
  • the following groups are particularly suitable: a hydrogen or halogen atom, a C1-C4-alkyl, e.g. Methyl-; a C2-C4 alkenyl, e.g. Allyl; a nitro; Amino-; Hydroxy-; Cyano; C1-C4 alkoxy, e.g. Methoxy, n-propyloxy; Benzyloxy-; 3-pyridinyloxy-; C1-C4 alkylsulfonyloxy, e.g.
  • N-C5-C6-cycloalkyl-N-C1-C4-alkyl-aminocarbonyl-C1-C4-alkoxy- e.g. N-cyclohexyl-N-methyl-aminocarbonyl-propyloxy group.
  • R5 is the C1-C4 alkyl group, e.g. Methyl group or a hydrogen atom is preferred.
  • R- the alkyl, such as e.g. Methyl group.
  • R5 and R6 can also represent a cyclopentyl or cyclohexyl ring together with the carbon atom to which they are attached.
  • X is a valence line.
  • Particularly preferred medicaments contain compounds of the general formula I in the R1 is a hydrogen atom, the nitro, amino, fluorine, chlorine, bromine, dimethylamino, diethylamino, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, allyl, hydroxy, methoxy, ethoxy, propyloxy, Allyloxy-, mercapto-, methylthio-, methylsulfinyl, methylsulfonyl-, methylsulfonyloxy-, cyanomethyloxy-, benzyloxy-, pyridinyloxy-, ethoxycarbonylmethyloxy-, carboxy-, ethyloxycarbonyl-, hydroxymethyl-, formylamino-, acetylamino-trifluoromethylsulfonylmethylsulfon
  • the present application also relates to new compounds of the formula I. in the R1, R2, R3, may be the same or different and each have a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, halogen, nitro, amino, formyl, hydroxy, Mercapto, cyano group, one by an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, benzyl, pyridinyl, alkylsulfonyl, trifluoromethylsulfonyl, alkylcarbonyl, cyanoalkyl, hydroxyalkyl, dialkylaminoalkyl, carboxyalkyl, Hydroxy group substituted by alkoxycarbonylalkyl or alkoxyalkyl group, one by one or two alkylsulfonyl, trifluoromethylsulfonyl, alkyl
  • the compounds of general formula I according to the invention can be prepared by methods known per se.
  • the synthesis from anilines and benzoic acids, as shown in Scheme 1 and Scheme 2, is particularly advantageous.
  • the anilines of the general formula II are used, in which R1, R2, R3 and X are the above have meanings mentioned, with the benzoic acids of the general formula III in which R4, R5 and R6 have the meanings given above and Y is the hydroxyl group, a halide such as chloride or bromide, an alkoxy or aryloxy group, an alkylcarbonyloxy or an arylcarbonyloxy group (Scheme 1):
  • the compound of the general formula III or IV are carboxylic acids.
  • the preferred method of reaction with the amines, general formula II or V, is to react approximately equimolar amounts of the amine and the acid in the presence of a dehydrating agent.
  • a dehydrating agent for example, polyphosphoric acid comes into consideration, which then also serves as a solvent.
  • the reactions take place between 50 ° C and 200 ° C.
  • the end products of the general formula I generally precipitate out after the addition of water and are purified by filtration by recrystallization or by column chromatography.
  • Another preferred method for the preparation of compounds of general formula I consists in reacting approximately equimolar amounts of the amine and the acid in a suitable solvent with approximately an equivalent amount of a halogenating agent, such as phosphorus trichloride, phosphorus pentachloride or thionyl chloride, at temperatures between room temperature and Reflux temperature of the mixture.
  • a halogenating agent such as phosphorus trichloride, phosphorus pentachloride or thionyl chloride
  • Suitable solvents are methylene chloride Carbon tetrachloride, diethyl ether, toluene, xylene or chlorobenzene.
  • the product precipitates out of the solution and is obtained by filtration. If necessary, the reaction mixture can be concentrated to a point where the product begins to precipitate out of solution.
  • Acidic cation exchangers sulfonium salts, sulfuric acid halides, 2-halopyridinium salts, phosphonium salts and dicyclohexylcarbodiimide are suitable as further condensing agents in this reaction.
  • the compounds of the general formula III or IV are carboxylic acid esters.
  • the reaction of approximately equimolar amounts of the amine and the ester in polyphosphoric acid at 50 ° C. to 200 ° C. is preferred, but it is also best in an inert solvent such as methylene chloride, benzene, toluene, chlorobenzene in the presence of a little more than one equivalent a base such as sodium ethanolate or butyllithium, or sodium hydride in dimethyl sulfoxide.
  • the compounds of the general formula III or IV are anhydrides. Since anhydrides are generally more reactive than carboxylic acids or carboxylic acid esters, the reaction with the amines of the general formula II or V can be carried out at somewhat lower temperatures. Is preferably carried out in an inert solvent such as dichloromethane, diethyl ether, benzene, toluene, at temperatures between room temperature and 60 ° C. The amine and the anhydride are combined in approximately equimolar amounts, an exothermic reaction generally starting. After the reaction has subsided, it is gently warmed for a while to complete the reaction.
  • anhydrides are generally more reactive than carboxylic acids or carboxylic acid esters
  • the reaction with the amines of the general formula II or V can be carried out at somewhat lower temperatures. Is preferably carried out in an inert solvent such as dichloromethane, diethyl ether, benzene, toluene, at temperatures between room temperature and 60 ° C.
  • the compounds of the general formula III or IV are carboxylic acid halides. This primarily means acid chlorides and bromides. Since the acid halides are more reactive than the carboxylic acids, esters or anhydrides, it is usually necessary to cool the reaction mixture. It is best to work at temperatures between -10 ° C and room temperature.
  • the preferred procedure is that, according to Schotten-Baumann, the acid chloride is slowly added dropwise to the aqueous solution of the amine of the general formula II or V, which also contains a base such as alkali metal hydroxides, sodium carbonate or pyridine, and then cooled for some time at room temperature lets stand.
  • This reaction is possible not only in water, but also in organic solvents such as methylene chloride, ether, benzene or toluene.
  • the amines can be acylated almost quantitatively by carboxylic acid chlorides by boiling the amine and the carboxylic acid chloride in an inert solvent such as methylene chloride, benzene or toluene until the evolution of gas has ended, which takes 1-24 hours.
  • an acid-binding agent such as triethylamine or pyridine is added in a slight excess, the reaction takes place at temperatures between -10 ° C. and room temperature.
  • the nitration is preferably carried out with nitric acid in sulfuric acid at temperatures between -20 ° C and + 50 ° C. However, it can also be carried out without sulfuric acid, or in its place in water, glacial acetic acid or acetic anhydride, or with N2O5 in CCl4 in the presence of P2O5.
  • Anhydrides such as acetyl nitrate or nitryl halides with FeCl3, methyl nitrate and BF3, or nitronium salts such as NO2BF4, NO2PF6 or NO2CF3SO3 can also serve as nitrating reagents.
  • a mixture of nitric acid and nitrous acid can also be used for nitration, which provides N2O4 as the actual nitrating species.
  • anilines of the general formula II and the benzoic acid of the general formula IV required as precursors for the preparation of compounds of the general formula I according to Scheme 1 and Scheme 2 are commercially available or known from the literature.
  • 4-tert-butylaniline of the anilines of the general formula V is commercially available, the others are known from the literature (cf. Jönsson, Acta chem. Scand. 8 (1954) 1211; Nerdel, Würgau, Liebigs Ann. Chem. 621 (1959) 34) , or can be prepared according to the methods described therein.
  • alkylations are carried out in an inert solvent such as dichloromethane, ether, toluene, xylene in the presence of a base such as sodium hydroxide solution or potassium hydroxide solution, if desired in the presence of a phase transfer catalyst such as tetrabutylammonium bromide and one equivalent of the alkylating agent IX, X or XI.
  • a base such as sodium hydroxide solution or potassium hydroxide solution
  • phase transfer catalyst such as tetrabutylammonium bromide and one equivalent of the alkylating agent IX, X or XI.
  • Compound VIII is known from the literature: JFCodington, E. Mosettig, J.Org.Chem. 17 (1952), 1035.
  • the compounds of the general formula III can be obtained by the reaction sequence diazotization, cyanation (Sandmeyer reaction) and saponification of the nitrile.
  • the compounds of the formula I can also be starting compounds for the preparation of other pharmaceutically active compounds which are the subject of German patent application P 3830060.5.
  • the substances of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and are shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as e.g. Olive oil, suspended or dissolved.
  • the substances of general formula I and their salts can be administered enterally or parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers or buffers.
  • Such additives are e.g. Tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation.
  • Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
  • the compounds of the formula I can be converted into their physiologically tolerable acid addition salts with inorganic or organic acids.
  • suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.
  • the compounds are usually applied in amounts of 10-1500 mg per day based on 75 kg of body weight. It is preferred to administer 1-2 tablets with an active substance content of 5-500 mg 2-3 times a day.
  • the tablets can also be delayed, which means that 1-2 tablets with 20-700 mg of active ingredient have to be given only once per day.
  • the active ingredient can also be given by injection 1-8 times a day or by continuous infusion, with amounts of 10-1000 mg per day usually being sufficient.
  • Example 2 Analogously to Example 1, 0.17 g of 4-methoxyaniline was reacted with 0.3 g of 4- (1-cyanoethyl) benzoic acid chloride and, after recrystallization from methanol, 0.23 g (60%) of the title compound was obtained as an off-white powder with a melting point of 176-178 ° C.
  • 4- (1-cyanoethyl) benzoic acid chloride was prepared as follows: 1.75 g (10 mmol) of methyl 4- (cyanomethyl) benzoate (JF Codington et al., J.Org.Chem. 17 (1952) 1035) and 0.28 g of tetrabutylammonium bromide in 9.7 ml of 50% sodium hydroxide solution were treated with 0.62 ml of iodomethane while cooling with ice. added dichloromethane and ice water after 1 h, separated off the dichloromethane, washed it with water until neutral, dried and removed the solvent in vacuo.
  • Example 2 Analogously to Example 1, 1.64 g (69%) of the title compound was obtained as a cream-colored powder with a melting point of 164-168 ° C. by reacting 1 g of 4-methoxyaniline with 1.86 g of 4- (1-cyano-1-methylethyl) benzoic acid chloride Recrystallization from methanol.
  • 4- (1-Cyano-1-methylethyl) benzoic acid chloride was prepared as follows: 0.9 g of methyl 4- (cyanomethyl) benzoate (JF Codington et al., J.Org.Chem. 17 (1952) 1035) and 0.15 g of tetrabutylammonium bromide in 5 ml of 50% sodium hydroxide solution were treated with 1 ml of iodomethane while cooling with ice. The mixture was stirred at room temperature for 16 h and worked up as described in Example 21. 1 g (96%) of methyl 4- (1-cyano-1-methylethyl) benzoate was obtained, mp 45-50 ° C.
  • Example 2 Analogously to Example 1, the title compound was obtained from 4- (1,1-dimethylethyl) aniline and 4-methoxybenzoic acid chloride in 65% yield with a melting point of 167-168 ° C.
  • Example 2 Analogously to Example 31, reaction of ethyl 4-bromobutyrate with 4- (1,1-dimethylethyl) -N- (4-hydroxyphenyl) benzamide (Example 2) gave the title compound in 56% yield with the mp. 100-101 ° C. after recrystallization from isopropanol.
  • Example 33 Analogously to Example 32, the compound from Example 33 was saponified and the title compound with the mp. 162-168 ° C. was obtained in 67% yield after recrystallization from ethyl acetate.
  • Example 2 Analogously to Example 1, the title compound was obtained from 4- (1,1-dimethylethyl) benzoic acid chloride and 4- (methoxyphenyl) methylamine in 71% yield with a melting point of 145-148 ° C. after recrystallization from isohexane.

Abstract

Drugs of the formula I <IMAGE> in which R1, R2 and R3 can be identical or different and each can be a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, halogen, nitro, amino, formyl, hydroxyl, mercapto, cyano group, a hydroxyl group substituted by an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, benzyl, pyridinyl, alkylsulphonyl, trifluoromethylsulphonyl, alkylcarbonyl, cyanoalkyl, hydroxyalkyl, dialkylaminoalkyl, aminocarbonylalkyl, dialkylaminocarbonylalkyl, N-cycloalkyl-N-alkylaminocarbonylalkyl, carboxyalkyl, alkoxycarbonylalkyl or alkoxyalkyl group, an amino group substituted by one or two alkylsulphonyl, trifluoromethylsulphonyl, alkylcarbonyl, formyl, aminocarbonyl, alkylaminocarbonyl or alkyl groups, a carbonyl group substituted by a hydroxyl, alkyl, alkoxy, amino, alkylamino or dialkylamino group, a sulphonyl group substituted by an amino, alkylamino, piperidino, morpholino or thiomorpholino group, or an alkylthio, alkylsulphinyl or alkylsulphonyl group, or in which two ortho substituents R2 and R3 form, together with the C atoms to which they are bonded, a five- or six-membered ring, X can be a bond, an alkylene group or, in the case where A is the carbonyl group -CO-, also the alkenylene group, and A and B are different and are the carbonyl group -CO- or the imino group -NH-, and R4 is a methyl, cyano, aminocarbonyl or aminomethyl group, R5 is a hydrogen atom or an alkyl group, R6 is an alkyl or cycloalkyl group, or R5 and R6 are, together with the C atom to which they are bonded, a cycloalkyl ring, the optically active forms thereof, the tautomers thereof and the physiologically tolerated salts thereof with inorganic and organic acids. The present invention also relates to phenylamides, process for the preparation of these compounds and the use thereof for preparing drugs, especially drugs acting to inhibit erythrocyte aggregation.

Description

Die vorliegende Erfindung betrifft Arzneimittel enthaltend Phenylamide der allgemeinen Formel I,

Figure imgb0001
in der
R₁, R₂, R₃, gleich oder verschieden sein können und je­weils ein Wasserstoffatom, eine Alkyl-, Alkenyl-, Alkinyl-, Cycloalkyl-, Cycloalkenyl-, Phenyl-, Halogen-, Nitro-, Amino-, Formyl-, Hydroxy-, Mercapto-, Cyanogruppe, eine durch eine Alkyl-, Alkenyl-, Alkinyl-, Cycloalkyl-, Cycloalkenyl-, Phenyl-, Benzyl-, Pyridinyl-, Alkyl­sulfonyl-, Trifluormethylsulfonyl-, Alkylcarbonyl-, Cyan­alkyl-, Hydroxyalkyl-, Dialkylaminoalkyl-, Aminocarbonyl­alkyl-, Dialkylaminocarbonylalkyl-, N-Cycloalkyl-N-alkyl­aminocarbonylalkyl-, Carboxyalkyl-, Alkoxycarbonylalkyl- oder Alkoxyalkylgruppe substituierte Hydroxygruppe, eine durch eine oder zwei Alkylsulfonyl-, Trifluormethyl­sulfonyl-, Alkylcarbonyl-, Formyl-, Aminocarbonyl-, Alkylaminocarbonyl- oder Alkylgruppen substituierte Aminogruppe, eine durch eine Hydroxy-, Alkyl-, Alkoxy-, Amino-, Alkylamino- oder Dialkylaminogruppe substituierte Carbonylgruppe, eine durch eine Amino-, Alkylamino-, Piperidino-, Morpholino- oder Thiomorpholinogruppe sub­stituierte Sulfonylgruppe, eine Alkylthio-, Alkylsulfinyl- oder Alkylsulfonylgruppe bedeuten können, oder in der zwei zueinander ortho-ständige Substituenten R₂ und R₃ zusammen mit den C-Atomen, an die sie gebunden sind, einen fünf- oder sechsgliedrigen Ring bilden,
X      eine Bindung, eine Alkylengruppe, oder für den Fall, daß A die Carbonylgruppe -CO- bedeutet, auch die Alkenylen­gruppe bedeuten kann, und
A und B verschieden sind und die Carbonylgruppe -CO- oder die Iminogruppe -NH- bedeuten, und
R₄      eine Methyl-, Cyano-, Aminocarbonyl- oder Aminomethyl­gruppe bedeutet,
R₅      ein Wasserstoffatom, oder eine Alkylgruppe bedeutet,
R₆      eine Alkyl- oder Cycloalkylgruppe bedeutet,
oder
R₅ und R₆ zusammen mit dem C-Atom, an das sie gebunden sind, einen Cycloalkylring bedeuten,
deren optisch aktiven Formen, deren Tautomere und deren physio­logisch verträglichen Salze anorganischer und organischer Säuren. Ferner bezieht sich die vorliegende Erfindung auf neue Phenylamide, Verfahren zur Herstellung dieser Verbindungen sowie deren Verwendung zur Herstellung von Arzneimitteln, ins­besondere von Arzneimitteln mit erythrozytenaggregationshemmen­der Wirkung.The present invention relates to medicaments containing phenylamides of the general formula I,
Figure imgb0001
 in the
R₁, R₂, R₃, may be the same or different and each have a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, halogen, nitro, amino, formyl, hydroxy, Mercapto, cyano group, one by an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, benzyl, pyridinyl, alkylsulfonyl, trifluoromethylsulfonyl, alkylcarbonyl, cyanoalkyl, hydroxyalkyl, dialkylaminoalkyl, Aminocarbonylalkyl, dialkylaminocarbonylalkyl, N-cycloalkyl-N-alkylaminocarbonylalkyl, carboxyalkyl, alkoxycarbonylalkyl or alkoxyalkyl group substituted hydroxy group, one substituted by one or two alkylsulfonyl, trifluoromethylsulfonyl, alkylcarbonyl, formyl, aminocarbonyl or alkylaminocated Amino group, one by a hydroxy, alkyl, alkoxy, Amino, alkylamino or dialkylamino group substituted carbonyl group, a sulfonyl group substituted by an amino, alkylamino, piperidino, morpholino or thiomorpholino group, an alkylthio, alkylsulfinyl or alkylsulfonyl group, or in which two mutually ortho substituents R₂ and R₃ together with the carbon atoms to which they are attached form a five- or six-membered ring,
X can be a bond, an alkylene group or, if A is the carbonyl group -CO-, can also be the alkenylene group, and
A and B are different and represent the carbonyl group -CO- or the imino group -NH-, and
R₄ represents a methyl, cyano, aminocarbonyl or aminomethyl group,
R₅ represents a hydrogen atom or an alkyl group,
R₆ represents an alkyl or cycloalkyl group,
or
R₅ and R₆ together with the carbon atom to which they are attached represent a cycloalkyl ring,
their optically active forms, their tautomers and their physiologically tolerable salts of inorganic and organic acids. Furthermore, the present invention relates to new phenylamides, processes for the preparation of these compounds and their use for the preparation of medicaments, in particular medicaments with an erythrocyte aggregation-inhibiting action.

Für den Fall, daß Verbindungen der allgemeinen Formel I ein Asymmetriezentrum oder eine Asymmetrieebene besitzen, sind auch die optisch aktiven Formen und racemischen Gemische dieser Verbindungen Gegenstand der Erfindung.In the event that compounds of the general formula I have an asymmetry center or an asymmetry plane, the optically active forms and racemic mixtures of these compounds are also a subject of the invention.

Arzneimittel, die diese Verbindungen enthalten, weisen wertvolle pharmakologische Eigenschaften auf, insbesondere wirken sie hemmend auf die Erythrozytenaggregation und können somit Verwendung finden zur Behandlung von Krankheiten, bei denen in der Pathogenese die Erythrozytenaggregation eine wichtige Rolle spielt, wie z.B. periphere, coronare und cerebrale Durchblutungsstörungen, Schockzustände, usw. Die Verbindungen beeinflussen darüberhinaus die Thrombozytenfunktion, steigern die Herzkraft und wirken blutdrucksenkend.Drugs containing these compounds have valuable pharmacological properties, in particular they have an inhibitory effect on erythrocyte aggregation and can thus be used for the treatment of diseases in which erythrocyte aggregation plays an important role in pathogenesis, such as e.g. peripheral, coronary and cerebral circulatory disorders, shock conditions, etc. The compounds also influence platelet function, increase heart strength and lower blood pressure.

Einige strukturell nahestehenden Verbindungen, die von der vorliegenden Erfindung nicht umfaßt werden, sind als Arznei­mittel bereits bekannt.Some structurally related compounds that are not encompassed by the present invention are already known as drugs.

So beschreiben die Patentanmeldungen CH 609,558 bzw. US 398522 (18. Sept. 1973, L.Givaudan et Cie.) die antibakterielle Wirkung von Verbindungen, in denen R₄, R₅, R₆ eine Methylgruppe, B eine Carbonyl-, A eine Iminogruppe -NH-, X einen Valenzstrich und einer der Substituenten R₁, R₂, R₃ in meta-Position des Phenylrings die Trifluormethylgruppe und die beiden anderen ein Wasserstoff- oder Halogenatom oder eine Trifluormethylgruppe darstellen, insbesondere die Verbindungen 4-(1,1-Dimethyl-ethyl)-N-[3-trifluormethyl)phenyl]benzamid und von N-[4-Chlor-3-trifluormethyl)phenyl)-4-(1,1-dimethylethyl)­benzamid.For example, patent applications CH 609,558 and US 398522 (Sept. 18, 1973, L. Givaudan et Cie.) Describe the antibacterial activity of compounds in which R₄, R₅, R₆ is a methyl group, B is a carbonyl group, A is an imino group -NH -, X represents a valence line and one of the substituents R₁, R₂, R₃ in the meta position of the phenyl ring represents the trifluoromethyl group and the other two represent a hydrogen or halogen atom or a trifluoromethyl group, especially the compounds 4- (1,1-dimethyl-ethyl) -N- [3-trifluoromethyl) phenyl] benzamide and of N- [4-chloro-3-trifluoromethyl) phenyl) -4- (1,1-dimethylethyl) benzamide.

Die Patentanmeldung US 4160097 (Westwood Pharmaceuticals, 3. Juli 1979) beschreibt die entzündungshemmende Wirkung von 4-­(1,1-Dimethylethyl)-N-[2-(1H-imidazol-1-yl)phenyl]benzamid.Patent application US 4160097 (Westwood Pharmaceuticals, July 3, 1979) describes the anti-inflammatory effect of 4- (1,1-dimethylethyl) -N- [2- (1H-imidazol-1-yl) phenyl] benzamide.

Von den folgenden Verbindungen, die von der vorliegenden Er­findung umfaßt werden, ist die Synthese beschrieben, jedoch nicht ihre Verwendung in Arzneimitteln:
N-[2-(Aminocarbonyl)phenyl]-4-(1,1-dimethylethyl)benzamid in der Patentanmeldung US 450870 (16.3.76, FMC Corp.);
4-(1,1-Dimethylethyl)-N-phenyl-benzamid in S.Ito et al., Nippon Noyaku Gakkashi 10, 697;
N-(2,6-Dihydroxyphenyl)-4-(1,1-dimethylethyl)benzamid in der Patentanmeldung GB 2018453 ( 14. Okt. 1979, Eastman Kodak);
4-(1,1-Dimethylethyl)-N-[2-(1-methylethoxy)phenyl]benzamid in der Patentanmeldung JP 77/496 (6. Jan. 1977), Kumiai Chemical Industry Co);
4-(1,1-Dimethylethyl)-N-[3-(1,1-dimethylethyl)-4-(octyl­oxy)phenyl]benzamid in der Patentanmeldung JP 55/6321 (17.1.1980, Konishiroku Photo Industry Co.);
2-[[4-(1,1-Dimethylethyl)benzoyl]amino]benzoesäure-methylester in K. Osann et al., Agric.Biol.Chem. 44, 2143;
N-(2,3-Dichlorphenyl)-4-(1,1-dimethylethyl)-benzamid in der Patentanmeldung JP 55/76851 (5. Okt. 1978, Hodogaya Chemical Co);
4-(1,1-Dimethylethyl)-N-[4-(1-methylethoxy)phenyl]benzamid in der Patentanmeldung JP 55/108846 (21.6.1980, Kumiai Chemical Ind.);
4-(1,1-Dimethylethyl)-N-[4-(1,1-dimethylethyl)phenyl]benzamid in F. Bell, J.A.Gibson, R.D. Wilson, J. Chem. Soc. 1956, 2335;
4-(1,1-Dimethylethyl)-N-(3-ethyl-4-hydroxyphenyl)benzamid in der Patentanmeldung ZA 68/5360 (19. Feb. 1970, ICI);
4-(1,1-Dimethylethyl)-N-[3-(1,1-dimethylethyl)-4-hydroxy-5-­methylphenyl]benzamid in der Patentanmeldung US 4025487 (24. Mai 1977, Ciba-Geigy);
4-(1,1-Dimethylethyl)-N-(2-hydroxy-4-nitrophenyl)benzamid, N-­(4-Amino-2-hydroxyphenyl)-4-(1,1-dimethylethyl)benzamid und 4-­(1,1-Dimethylethyl)-N-[2-hydroxy-4-[(2-methyl-1-oxo-2-­propenyl)amino]phenyl]benzamid in der Patentanmeldung DE 2156480 (6. Juni 1972, Agfa);
N-(5-Chlor-2-hydroxy-4-nitrophenyl)-4-(1,1-dimethylethyl)­benzamid und N-(4-Amino-5-chlor-2-hydroxyphenyl)-4-(1,1-di­methylethyl)benzamid in der Patentanmeldung JP 59/146050 21. August 1984, Fuji);
N-[4-(1,1-Dimethylethyl)phenyl]benzamid in R.M. Acheson, C.W.C. Harvey, J. Chem. Soc., Perkin I, 1976, 465.
N-[4-(1,1-Dimethylethyl)phenyl]-4-methyl-benzamid in der Patentanmeldung JP 58/187 391 (1. Nov. 1983, Fuji).
3-[[4-(1,1-dimethylethyl)benzoyl]amino]-4-methyl-benzoe­säuremethylester und 4-Amino-3-[[4-(1,1-dimethylethyl)­benzoyl]amino]benzoesäuremethylester in der Patentanmeldung BE 903254 (18. März 1986, C.I.R.D.).The following compounds, which are encompassed by the present invention, describe the synthesis, but not their use in drugs:
N- [2- (aminocarbonyl) phenyl] -4- (1,1-dimethylethyl) benzamide in patent application US 450870 (3/16/76, FMC Corp.);
4- (1,1-dimethylethyl) -N-phenyl-benzamide in S.Ito et al., Nippon Noyaku Gakkashi 10 , 697;
N- (2,6-dihydroxyphenyl) -4- (1,1-dimethylethyl) benzamide in patent application GB 2018453 (Oct. 14, 1979, Eastman Kodak);
4- (1,1-dimethylethyl) -N- [2- (1-methylethoxy) phenyl] benzamide in patent application JP 77/496 (Jan. 6, 1977), Kumiai Chemical Industry Co);
4- (1,1-dimethylethyl) -N- [3- (1,1-dimethylethyl) -4- (octyloxy) phenyl] benzamide in patent application JP 55/6321 (1/17/1980, Konishiroku Photo Industry Co.);
2 - [[4- (1,1-Dimethylethyl) benzoyl] amino] benzoic acid methyl ester in K. Osann et al., Agric.Biol.Chem. 44 , 2143;
N- (2,3-dichlorophenyl) -4- (1,1-dimethylethyl) benzamide in patent application JP 55/76851 (Oct. 5, 1978, Hodogaya Chemical Co);
4- (1,1-dimethylethyl) -N- [4- (1-methylethoxy) phenyl] benzamide in patent application JP 55/108846 (June 21, 1980, Kumiai Chemical Ind.);
4- (1,1-dimethylethyl) -N- [4- (1,1-dimethylethyl) phenyl] benzamide in F. Bell, JAGibson, RD Wilson, J. Chem. Soc. 1956 , 2335;
4- (1,1-dimethylethyl) -N- (3-ethyl-4-hydroxyphenyl) benzamide in patent application ZA 68/5360 (Feb. 19, 1970, ICI);
4- (1,1-dimethylethyl) -N- [3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] benzamide in patent application US 4025487 (May 24, 1977, Ciba-Geigy);
4- (1,1-dimethylethyl) -N- (2-hydroxy-4-nitrophenyl) benzamide, N- (4-amino-2-hydroxyphenyl) -4- (1,1-dimethylethyl) benzamide and 4- (1 , 1-Dimethylethyl) -N- [2-hydroxy-4 - [(2-methyl-1-oxo-2-propenyl) amino] phenyl] benzamide in patent application DE 2156480 (June 6, 1972, Agfa);
N- (5-chloro-2-hydroxy-4-nitrophenyl) -4- (1,1-dimethylethyl) benzamide and N- (4-amino-5-chloro-2-hydroxyphenyl) -4- (1,1- dimethylethyl) benzamide in patent application JP 59/146050 August 21, 1984, Fuji);
N- [4- (1,1-Dimethylethyl) phenyl] benzamide in RM Acheson, CWC Harvey, J. Chem. Soc., Perkin I, 1976, 465.
N- [4- (1,1-Dimethylethyl) phenyl] -4-methyl-benzamide in patent application JP 58/187 391 (Nov. 1, 1983, Fuji).
Methyl 3 - [[4- (1,1-dimethylethyl) benzoyl] amino] -4-methyl-benzoate and methyl 4-amino-3 - [[4- (1,1-dimethylethyl) benzoyl] amino] benzoate in the patent application BE 903254 (March 18, 1986, CIRD).

Die "Alkyl-", "Alkenyl-" oder "Alkinyl-"teile der bei den Substituenten R₁, R₂, R₃, R₅ und R₆ genannten Gruppen können 1-­6 bzw. 2-6 Kohlenstoffatome enthalten und geradkettig oder verzweigt sein. Bevorzugt kommen geradkettige Derivate mit 1-4 bzw. 2-4 Kohlenstoffatome in Frage.The "alkyl", "alkenyl" or "alkynyl" parts of the groups mentioned for the substituents R₁, R₂, R₃, R₅ and R₆ can contain 1-6 or 2-6 carbon atoms and be straight-chain or branched. Straight-chain derivatives with 1-4 or 2-4 carbon atoms are preferred.

Beispielsweise versteht man darunter die Methyl-, Ethyl-, n-­Propyl-, i-Propyl-, n-Butyl-, i-Butyl-, tert.-Butyl-, Pentyl- und Hexylgruppe, die Methoxy-, Ethoxy-, n-Propyloxy-, i-Propyl­oxy-, Allyloxy-, i-Butenyloxy-, Propinyloxy-, n-Butyloxy-, tert.-Butyloxy-, i-Butyloxy-, n-Pentyloxy-, n-Hexyloxy-, Methylsulfonyloxy-, Ethylsulfonyloxy-, n-Propylsulfonyloxy-, i-­Propylsulfonyloxy-, Methylcarbonyloxy-, Ethylcarbonyloxy-, Propylcarbonyloxy-, Cyanethyloxy-, Carboxyethoxy-, Ethoxy­carbonylethoxy-, Methoxycarbonylethoxy-, Methoxyethyloxy-, Dimethylamino-, Diethylamino-, Acetylamino-, Propionylamino-, Methylsulfonylamino-, Ethylsulfonylamino-, n-Propylsulfonyl­amino-, i-Propylsulfonylamino-, Acetylaminocarbonylamino-, Propionylaminocarbonylamino-, Acetyl-, Propionyl-, Ethoxy­carbonyl-, Propyloxycarbonyl-, Butyloxycarbonyl-, Methylamino­carbonyl-, Ethylaminocarbonyl-, Propylaminocarbonyl-, Dimethyl­aminocarbonyl-, Diethylaminocarbonyl-, Methylaminosulfonyl-, Ethylaminosulfonyl-, Methylthio-, Ethylthio-, Propylthio-, Methylsulfinyl-, Ethylsulfinyl-, Propylsulfinyl-, Methyl­sulfonyl-, Ethylsulfonyl- oder Propylsulfonylgruppe.For example, it means the methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl and hexyl group, the methoxy, ethoxy, n Propyloxy, i-propyloxy, allyloxy, i-butenyloxy, propinyloxy, n-butyloxy, tert-butyloxy, i-butyloxy, n-pentyloxy, n-hexyloxy, methylsulfonyloxy, ethylsulfonyloxy -, n-Propylsulfonyloxy-, i-Propylsulfonyloxy-, Methylcarbonyloxy-, Ethylcarbonyloxy-, Propylcarbonyloxy-, Cyanethyloxy-, Carboxyethoxy-, Ethoxycarbonylethoxy-, Methoxycarbonylethoxy-, Methoxyethyloxy-, Dimethylamino-, Diethylamino-, Methylsylamino-, Ethylsylamino- , Ethylsulfonylamino-, n-propylsulfonylamino-, i-propylsulfonylamino-, acetylaminocarbonylamino-, propionylaminocarbonylamino-, acetyl-, propionyl-, ethoxycarbonyl-, propyloxycarbonyl-, butyloxycarbonyl-, methylaminocarbonyl-, ethylaminylaminyl, ethylaminylaminylamine, ethylaminylaminylamine, ethylaminylamine, Methylaminosulfonyl, ethylaminosulfonyl, meth ylthio, ethylthio, propylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl, methylsulfonyl, ethylsulfonyl or propylsulfonyl group.

Weitere Substituenten R₁, R₂, R₃, die bevorzugt sind, sind die Phenylgruppe, für den Fall, daß R₁, R₂, R₃ eine substituierte Hydroxygruppe darstellt, die Phenyloxy-, Pyridinyloxy- und die Benzyloxygruppe; weiterhin Halogenatome wie Fluor, Chlor oder Brom, die Nitro-, Amino-, Formyl-, Hydroxy-, Mercapto-, Cyano-, Formylamino-, Carboxy-, Piperidinosulfonyl-, Morpholino­sulfonyl- und die Thiomorpholinosulfonylgruppe und das Wasser­stoffatom.Further substituents R₁, R₂, R₃ which are preferred are the phenyl group, in the event that R₁, R₂, R₃ represents a substituted hydroxy group, the phenyloxy, pyridinyloxy and the benzyloxy group; further halogen atoms such as fluorine, chlorine or bromine, the nitro, amino, formyl, hydroxy, mercapto, cyano, formylamino, carboxy, piperidinosulfonyl, morpholinosulfonyl and the thiomorpholinosulfonyl group and the hydrogen atom.

Bilden ortho-ständige Substituenten R₁ und R₂ zusammen mit den C-Atomen, an die sie gebunden sind einen fünf- oder sechs­gliedrigen Ring, so resultieren daraus Bicyclen, unter denen man die Methylendioxyphenyl, die Ethylendioxyphenyl- und die Tetrahydronaphthylgruppe versteht.Form ortho-standing substituents R₁ and R₂ together with the carbon atoms to which they are attached a five- or six-membered ring, resulting in bicycles, including the methylenedioxyphenyl, the ethylenedioxyphenyl and the tetrahydronaphthyl group.

Insbesondere sind bevorzugt für
R₁ das Wasserstoffatom, die Methyl-, Ethyl-, n-Propyl-, i-­Propyl-, n-Butyl-, tert.-Butyl-, Fluor-, Chlor-, Brom-, Nitro-, Amino-, Hydroxy-, Mercapto-, Formyl-, Cyano-, Formylamino-, Carboxy-, C₁-C₄-Alkyl, C₁-C₄-Alkoxy-, Allyloxy-, i-Butenyloxy-, Propargyloxy-, Cyanmethyloxy-, Ethoxycarbonylmethoxy-, Amino­carbonyl-, Methoxycarbonyl-, Ethoxycarbonyl-, C₁-C₃-Dialkyl­amino-, C₁-C₃-Alkylmercapto-, C₁-C₃-Alkylsulfinyl-, C₁-C₃-­Alkylsulfonyl-, C₁-C₃-Alkylsulfonyloxy-, die Phenyl-, Phenyl­oxy-, Pyridinyloxy- und die Benzyloxygruppe,
für R₂ das Wasserstoffatom, eine C₁-C₄-Alkyl-, C₁-C₄-Alkoxy-, C₁-C₃-Dialkylamino-, Fluor-, Chlor-, Brom- und die Hydroxy­gruppe,
für R₃ das Wasserstoffatom, eine Hydroxy- und Methoxygruppe.In particular, are preferred for
R₁ is the hydrogen atom, the methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, fluorine, chlorine, bromine, nitro, amino, hydroxy, Mercapto, formyl, cyano, formylamino, carboxy, C₁-C₄ alkyl, C₁-C₄ alkoxy, allyloxy, i-butenyloxy, propargyloxy, cyanomethyloxy, ethoxycarbonylmethoxy, aminocarbonyl, methoxycarbonyl , Ethoxycarbonyl-, C₁-C₃-dialkylamino-, C₁-C₃-alkylmercapto-, C₁-C₃-alkylsulfinyl, C₁-C₃-alkylsulfonyl-, C₁-C₃-alkylsulfonyloxy-, the phenyl, phenyloxy, pyridinyloxy and the Benzyloxy group,
for R₂ the hydrogen atom, a C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₃-dialkylamino, fluorine, chlorine, bromine and the hydroxy group,
for R₃ the hydrogen atom, a hydroxy and methoxy group.

Bevorzugte monosubstituierte Phenyle sind Fluor-, Chlor-, Brom-, Hydroxy-, Amino-, Cyano-, C₁-C₄-Alkyl-, C₁-C₄-Alkoxy-, C₂-C₄-Alkenyloxy-, Propargyloxy-, Cyanmethoxy-, Methoxy­carbonylmethyloxy-, Nitro-, Aminocarbonyl-, Methoxycarbonyl-, Ethoxycarbonyl-, C₁-C₃-Dialkylamino-, C₁-C₃-Alkylmercapto-, C₁-­C₃-Alkylsulfinyl-, C₁-C₃-Alkylsulfonyl-, C₁-C₃-Alkylsulfonyl­oxy-, Trifluormethylsulfonyloxy- wobei der Substituent in 2-, 3- oder 4-Stellung stehen kann.Preferred monosubstituted phenyls are fluorine, chlorine, bromine, hydroxy, amino, cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, propargyloxy, cyanomethoxy, methoxycarbonylmethyloxy -, Nitro, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, C₁-C₃-dialkylamino, C₁-C₃-alkylmercapto-, C₁-C₃-alkylsulfinyl, C₁-C₃-alkylsulfonyl-, C₁-C₃-alkylsulfonyloxy-, trifluoromethylsulfonyl - The substituent can be in the 2-, 3- or 4-position.

Bevorzugte disubstituierte Phenyle enthalten als Substituenten C₁-C₄-Alkyl-, Chlor-, Hydroxy-, C₁-C₄-Alkoxy-, Methylendioxy-, C₁-C₄-Alkylsulfonyloxy-, Trifluormethylsulfonyloxy-, C₁-C₄-­Alkythio-, C₁-C₄-Alkylsulfinyl-, C1-C4-Alkylsulfonyl-, C₁-C₄-­Alkylsulfonylamino-, Trifluormethylsulfonylamino-, Cyan­methyloxy- oder Methoxycarbonylmethyloxygruppe, wobei die Gruppen gleich oder verschieden sein können und in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- und 3,5-Stellung stehen können.Preferred disubstituted phenyls contain, as substituents, C₁-C₄-alkyl, chlorine, hydroxy, C₁-C₄-alkoxy, methylenedioxy, C₁-C₄-alkylsulfonyloxy-, trifluoromethylsulfonyloxy-, C₁-C₄-alkythio-, C₁-C₄- Alkylsulfinyl, C1-C4-alkylsulfonyl, C₁-C₄-alkylsulfonylamino, trifluoromethylsulfonylamino, cyanomethyloxy or methoxycarbonylmethyloxy group, where the groups can be identical or different and are in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-position can stand.

Bevorzugte trisubstituierte Phenyle weisen als Substituenten C₁-C₄-Alkyl-, C₁-C₄-Alkenyl-, C₁-C₄-Alkenyloxy- und Chlor­gruppen auf, wobei die Reste gleich oder verschieden sein kön­nen und in 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- oder 3,4,5-­Stellung stehen können.Preferred trisubstituted phenyls have as substituents C₁-C₄-alkyl, C₁-C₄-alkenyl, C₁-C₄-alkenyloxy and chlorine groups, where the radicals can be the same or different and in 2,3,4-, 2,3 , 5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-position can stand.

Bedeutet in der allgemeinen Formel I X eine Alkylengruppe, so sind darunter die Methylen-, Ethylen-, Propylen- und die Butylengruppe zu verstehen. Als Alkenylengruppe kommt ins­besondere die Vinylengruppe in Frage.If in the general formula I X denotes an alkylene group, it means the methylene, ethylene, propylene and the butylene group. The vinylene group is particularly suitable as the alkenylene group.

Bedeutet in der allgemeinen Formel I R₅ oder R₆ eine Alkyl­gruppe, so versteht man darunter geradkettige oder verzweigte Alkylketten mit 1-6 C-Atomen. Besonders bevorzugt ist die Methyl-, Ethyl-, Propyl- und die Butylgruppe.If R₅ or R₆ in the general formula I denotes an alkyl group, this means straight-chain or branched alkyl chains with 1-6 C atoms. The methyl, ethyl, propyl and butyl groups are particularly preferred.

Bedeutet in der allgemeinen Formel I R₆ eine Cycloalkylgruppe, so sind bevorzugt die Cyclopropyl-, Cyclobutyl-, Cyclopentyl- und die Cyclohexylgruppe.In the general formula I R₆ denotes a cycloalkyl group, the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups are preferred.

Bilden in der allgemeinen Formel I R₅ und R₆ zusammen mit dem C-Atom, an das sie gebunden sind, einen Cycloalkylring, so sind bevorzugt der Cyclopropyl-, Cyclobutyl-, Cyclopentyl- und Cyclohexylring.Form in the general formula I R₅ and R₆ together with the carbon atom to which they are attached, a cycloalkyl ring, so the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl ring are preferred.

Für den Fall, daß R₁ in ortho-Position des Phenylrings steht, kommen im Sinne der vorliegenden Erfindung insbesondere für R₁ ein Wasserstoff- oder Chloratom, eine C₁-C₄-Alkoxy-, wie z.B. Methoxy-, und die Nitrogruppe in Frage.In the event that R₁ is in the ortho position of the phenyl ring, in the sense of the present invention there is in particular for R₁ a hydrogen or chlorine atom, a C₁-C₄ alkoxy such as Methoxy, and the nitro group in question.

Stellt R₂ den Substituenten in meta-Position dar, so ist dies insbesondere ein Wasserstoff- oder Chloratom, oder eine C₁-C₄-­Alkoxy- wie z.B. Methoxygruppe.R₂ represents the substituent in the meta position, this is in particular a hydrogen or chlorine atom, or a C₁-C₄ alkoxy such as methoxy group.

Für den Fall, daß R₃ in para-Position des Phenylrings steht, kommen insbesondere folgende Gruppen in Frage: ein Wasserstoff- oder Halogenatom, eine C₁-C₄-Alkyl-, z.B. Methyl-; eine C₂-C₄-­Alkenyl-, wie z.B. Allyl-; eine Nitro-; Amino-; Hydroxy-; Cyano-; C₁-C₄-Alkoxy-, wie z.B. Methoxy-, n-Propyloxy-; Benzyl­oxy-; 3-Pyridinyloxy-; C₁-C₄-Alkylsulfonyloxy-, wie z.B. Methylsulfonyloxy-; Hydroxy-C₁-C₄-alkyloxy-, wie z.B. Hydroxy­ethyloxy-; Carboxy-C₁-C₄-alkoxy-, wie z.B. Carboxymethyloxy- oder Carboxypropyloxy-; eine C₁-C₄-Alkoxycarbonyl-C₁-C₄-­alkoxy-, wie z.B. Ethoxycarbonylmethyloxy- oder Ethoxycarbonyl­propyloxy-; eine Di-C₁-C₄-alkylamino-, wie z.B. Dimethylamino-; oder N-C₅-C₆-Cycloalkyl-N-C₁-C₄-alkyl-aminocarbonyl-C₁-C₄-­alkoxy-, wie z.B. N-Cyclohexyl-N-methyl-aminocarbonyl-propyl­oxygruppe.In the event that R₃ is in the para position of the phenyl ring, the following groups are particularly suitable: a hydrogen or halogen atom, a C₁-C₄-alkyl, e.g. Methyl-; a C₂-C₄ alkenyl, e.g. Allyl; a nitro; Amino-; Hydroxy-; Cyano; C₁-C₄ alkoxy, e.g. Methoxy, n-propyloxy; Benzyloxy-; 3-pyridinyloxy-; C₁-C₄ alkylsulfonyloxy, e.g. Methylsulfonyloxy-; Hydroxy-C₁-C₄-alkyloxy, e.g. Hydroxyethyloxy-; Carboxy-C₁-C₄-alkoxy, e.g. Carboxymethyloxy or carboxypropyloxy; a C₁-C₄ alkoxycarbonyl-C₁-C₄ alkoxy, e.g. Ethoxycarbonylmethyloxy or ethoxycarbonylpropyloxy; a di-C₁-C₄ alkylamino, e.g. Dimethylamino; or N-C₅-C₆-cycloalkyl-N-C₁-C₄-alkyl-aminocarbonyl-C₁-C₄-alkoxy-, e.g. N-cyclohexyl-N-methyl-aminocarbonyl-propyloxy group.

Für R₄ kommt insbesondere die Methyl- oder Cyanogruppe in Frage. In der Definition von R₅ ist die C₁-C₄-Alkylgruppe, wie z.B. Methylgruppe oder ein Wasserstoffatom bevorzugt.The methyl or cyano group is particularly suitable for R₄. In the definition of R₅ is the C₁-C₄ alkyl group, e.g. Methyl group or a hydrogen atom is preferred.

Für R₆ eignet sich vor allem die Alkyl-, wie z.B. Methylgruppe. R₅ und R₆ können aber auch gemeinsam mit dem C-Atom, an das sie gebunden sind, einen Cyclopentyl- oder Cyclohexylring dar­stellen.For R- the alkyl, such as e.g. Methyl group. R₅ and R₆ can also represent a cyclopentyl or cyclohexyl ring together with the carbon atom to which they are attached.

Die bevorzugte Bedeutung von X ist ein Valenzstrich.The preferred meaning of X is a valence line.

Besonders bevorzugte Arzneimittel enthalten Verbindungen der allgemeinen Formel I,
in der
R₁      ein Wasserstoffatom, die Nitro-, Amino-, Fluor-, Chlor-, Brom-, Dimethylamino-, Diethylamino-, Cyano-, Methyl-, Ethyl-, n-Propyl-, i-Propyl-, n-Butyl-, i-Butyl-, tert.-­Butyl-, Allyl-, Hydroxy-, Methoxy-, Ethoxy-, Propyloxy-, Allyloxy-, Mercapto-, Methylthio-, Methylsulfinyl-, Methylsulfonyl-, Methylsulfonyloxy-, Cyanmethyloxy-, Benzyloxy-, Pyridinyloxy-, Ethoxycarbonylmethyloxy-, Carboxy-, Ethyloxycarbonyl-, Hydroxymethyl-, Formylamino-, Acetylamino-, Methylsulfonylamino- und die Trifluormethyl­sulfonylaminogruppe bedeuten kann,
R₂      ein Wasserstoffatom, die Methyl-, Ethyl-, n-Propyl-, i-­Propyl-, tert.-Butyl-, Chlor-, Methoxy-, Hydroxy- oder Dimethylaminogruppe bedeutet,
R₃      ein Wasserstoffatom, die Hydroxy- oder Methoxygruppe bedeutet,
X      eine Bindung, die Ethylengruppe oder für den Fall, daß A die Carbonylgruppe bedeutet, auch die Vinylengruppe bedeutet,
A und B verschieden sind und die Imino- und die Carbonylgruppe bedeuten,
R₄      die Methyl-, Cyano-, Aminocarbonyl- oder Aminomethylgruppe bedeutet,
R₅      ein Wasserstoffatom, die Methyl- oder Ethylgruppe bedeutet,
R₆      die Methylgruppe, Ethylgruppe oder Cyclopentylgruppe bedeutet, oder
R₅ und R₆ zusammen mit dem C-Atom, an das sie gebunden sind, die Cyclopentylgruppe bedeuten.Particularly preferred medicaments contain compounds of the general formula I
in the
R₁ is a hydrogen atom, the nitro, amino, fluorine, chlorine, bromine, dimethylamino, diethylamino, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, allyl, hydroxy, methoxy, ethoxy, propyloxy, Allyloxy-, mercapto-, methylthio-, methylsulfinyl, methylsulfonyl-, methylsulfonyloxy-, cyanomethyloxy-, benzyloxy-, pyridinyloxy-, ethoxycarbonylmethyloxy-, carboxy-, ethyloxycarbonyl-, hydroxymethyl-, formylamino-, acetylamino-trifluoromethylsulfonylmethylsulfonyl, methylsulfonyl can mean
R₂ is a hydrogen atom which means methyl, ethyl, n-propyl, i-propyl, tert-butyl, chlorine, methoxy, hydroxyl or dimethylamino group,
R₃ is a hydrogen atom, which means hydroxyl or methoxy group,
X represents a bond which represents the ethylene group or, if A represents the carbonyl group, also the vinylene group,
A and B are different and denote the imino and the carbonyl group,
R₄ represents the methyl, cyano, aminocarbonyl or aminomethyl group,
R₅ is a hydrogen atom which means methyl or ethyl group,
R₆ represents the methyl group, ethyl group or cyclopentyl group, or
R₅ and R₆ together with the carbon atom to which they are attached mean the cyclopentyl group.

Gegenstand der vorliegenden Anmeldung sind auch neue Ver­bindungen der Formel I

Figure imgb0002
in der
R₁, R₂, R₃, gleich oder verschieden sein können und je­weils ein Wasserstoffatom, eine Alkyl-, Alkenyl-, Alkinyl -, Cycloalkyl-, Cycloalkenyl-, Phenyl-, Halogen-, Nitro-, Amino-, Formyl-, Hydroxy-, Mercapto-, Cyanogruppe, eine durch eine Alkyl-, Alkenyl-, Alkinyl-, Cycloalkyl-, Cycloalkenyl-, Benzyl-, Pyridinyl-, Alkylsulfonyl-, Tri­fluormethylsulfonyl-, Alkylcarbonyl-, Cyanalkyl-, Hydroxy­alkyl-, Dialkylaminoalkyl-, Carboxyalkyl-, Alkoxycarbonyl­alkyl- oder Alkoxyalkylgruppe substituierte Hydroxygruppe, eine durch eine oder zwei Alkylsulfonyl-, Trifluormethyl­sulfonyl-, Alkylcarbonyl-, Formyl-, Aminocarbonyl-, Alkyl­aminocarbonyl- oder Alkylgruppen substituierte Amino­gruppe, eine durch eine Hydroxy-, Alkyl-, Alkoxy-, Amino-, Alkylamino- oder Dialkylaminogruppe substituierte Carbonylgruppe, eine durch eine Amino-, Alkylamino-, Piperidino-, Morpholino- oder Thiomorpholinogruppe sub­stituierte Sulfonylgruppe, eine Alkylthio-, Alkylsulfinyl- oder Alkylsulfonylgruppe bedeuten können, oder in der zwei zueinander ortho-ständige Substituenten R₂ und R₃ zusammen mit den C-Atomen, an die sie gebunden sind, einen fünf- oder sechsgliedrigen Ring bilden,
X      eine Bindung, eine Alkylengruppe, oder für den Fall, daß A die Carbonylgruppe -CO- bedeutet, auch die Vinylengruppe bedeuten kann, und
A und B verschieden sind und die Carbonylgruppe -CO- oder die Iminogruppe -NH- bedeuten, und
R₄      eine Methyl-, Cyano-, Aminocarbonyl- oder Aminomethyl­gruppe bedeutet,
R₅      ein Wasserstoffatom, oder eine Alkylgruppe bedeutet,
R₆      eine Alkyl- oder Cycloalkylgruppe bedeutet,
oder
R₅ und R₆ zusammen mit dem C-Atom, an das sie gebunden sind, einen Cycloalkylring bedeuten,
deren Tautomere und deren physiologisch verträglichen Salze sowie deren optische Isomeren, mit Ausnahme folgender Ver­bindungen:
4-(1,1-Dimethyl-ethyl)-N-[3-trifluormethyl)phenyl]benzamid
N-[4-Chlor-3-trifluormethyl)phenyl)-4-(1,1-dimethylethyl)­benzamid
4-(1,1-Dimethylethyl)-N-[2-(1H-imidazol-1-yl)phenyl]benzamid
N-[2-(Aminocarbonyl)phenyl]-4-(1,1-dimethylethyl)benzamid
4-(1,1-Dimethylethyl)-N-phenyl-benzamid
N-(2,6-Dihydroxyphenyl)-4-(1,1-dimethylethyl)benzamid
4-(1,1-Dimethylethyl)-N-[2-(1-methylethoxy)phenyl]benzamid
2-[[4-(1,1-Dimethylethyl)benzoyl]amino]benzoesäure-methylester
N-(2,3-Dichlorphenyl)-4-(1,1-dimethylethyl)-benzamid
4-(1,1-Dimethylethyl)-N-[4-(1-methylethoxy)phenyl]benzamid
4-(1,1-Dimethylethyl)-N-[4-(1,1-dimethylethyl)phenyl]benzamid
4-(1,1-Dimethylethyl)-N-(3-ethyl-4-hydroxyphenyl)benzamid
4-(1,1-Dimethylethyl)-N-[3-(1,1-dimethylethyl)-4-hydroxy-5-­methylphenyl]benzamid
4-(1,1-Dimethylethyl)-N-(2-hydroxy-4-nitrophenyl)benzamid
N-(5-Chlor-2-hydroxy-4-nitrophenyl)-4-(1,1-dimethylethyl)­benzamid
N-(4-Amino-5-chlor-2-hydroxyphenyl)-4-(1,1-dimethylethyl)­benzamid
N-[4-(1,1-Dimethylethyl)phenyl]benzamid
N-[4-(1,1-Dimethylethyl)phenyl]-4-methyl-benzamid
3-[[4-(1,1-dimethylethyl)benzoyl]amino]-4-methyl-benzoe­säuremethylester
4-Amino-3-[[4-(1,1-dimethylethyl)benzoyl]amino]benzoesäure­methylester
The present application also relates to new compounds of the formula I.
Figure imgb0002
 in the
R₁, R₂, R₃, may be the same or different and each have a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, halogen, nitro, amino, formyl, hydroxy, Mercapto, cyano group, one by an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, benzyl, pyridinyl, alkylsulfonyl, trifluoromethylsulfonyl, alkylcarbonyl, cyanoalkyl, hydroxyalkyl, dialkylaminoalkyl, carboxyalkyl, Hydroxy group substituted by alkoxycarbonylalkyl or alkoxyalkyl group, one by one or two alkylsulfonyl, trifluoromethylsulfonyl, alkylcarbonyl, formyl, aminocarbonyl, alkylaminocarbonyl or alkyl groups, amino group substituted by hydroxy, alkyl, alkoxy, amino, alkylamino - or a dialkylamino group substituted carbonyl group, a sulfonyl group substituted by an amino, alkylamino, piperidino, morpholino or thiomorpholino group, an alkylthio, alkylsulfinyl or alkylsulfonyl group, or in which two mutually ortho-standing substituents R₂ and R₃ together with the C atoms to which they are attached form a five- or six-membered ring,
X can be a bond, an alkylene group or, if A is the carbonyl group -CO-, can also be the vinylene group, and
A and B are different and represent the carbonyl group -CO- or the imino group -NH-, and
R₄ represents a methyl, cyano, aminocarbonyl or aminomethyl group,
R₅ represents a hydrogen atom or an alkyl group,
R₆ represents an alkyl or cycloalkyl group,
or
R₅ and R₆ together with the carbon atom to which they are attached represent a cycloalkyl ring,
their tautomers and their physiologically acceptable salts and their optical isomers, with the exception of the following compounds:
4- (1,1-dimethyl-ethyl) -N- [3-trifluoromethyl) phenyl] benzamide
N- [4-chloro-3-trifluoromethyl) phenyl) -4- (1,1-dimethylethyl) benzamide
4- (1,1-dimethylethyl) -N- [2- (1H-imidazol-1-yl) phenyl] benzamide
N- [2- (aminocarbonyl) phenyl] -4- (1,1-dimethylethyl) benzamide
4- (1,1-dimethylethyl) -N-phenylbenzamide
N- (2,6-dihydroxyphenyl) -4- (1,1-dimethylethyl) benzamide
4- (1,1-dimethylethyl) -N- [2- (1-methylethoxy) phenyl] benzamide
2 - [[4- (1,1-Dimethylethyl) benzoyl] amino] benzoic acid methyl ester
N- (2,3-dichlorophenyl) -4- (1,1-dimethylethyl) benzamide
4- (1,1-dimethylethyl) -N- [4- (1-methylethoxy) phenyl] benzamide
4- (1,1-dimethylethyl) -N- [4- (1,1-dimethylethyl) phenyl] benzamide
4- (1,1-dimethylethyl) -N- (3-ethyl-4-hydroxyphenyl) benzamide
4- (1,1-dimethylethyl) -N- [3- (1,1-dimethylethyl) -4-hydroxy-5-methylphenyl] benzamide
4- (1,1-dimethylethyl) -N- (2-hydroxy-4-nitrophenyl) benzamide
N- (5-chloro-2-hydroxy-4-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-Amino-5-chloro-2-hydroxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- [4- (1,1-Dimethylethyl) phenyl] benzamide
N- [4- (1,1-Dimethylethyl) phenyl] -4-methyl-benzamide
3 - [[4- (1,1-dimethylethyl) benzoyl] amino] -4-methylbenzoic acid methyl ester
4-Amino-3 - [[4- (1,1-dimethylethyl) benzoyl] amino] benzoic acid methyl ester

Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können nach an sich bekannten Methoden hergestellt werden. Von besonderem Vorteil ist die Synthese aus Anilinen und Benzoe­säuren, wie sie in Schema 1 und Schema 2 dargestellt ist. Für Verbindungen der allgemeinen Formel I, in der A die Aminogruppe -NH- bedeutet und B die Carbonylgruppe -CO- (= allgemeine Formel Ia), setzt man die Aniline der allgemeinen Formel II, in der R₁, R₂, R₃ und X die oben genannten Bedeutungen haben, mit den Benzoesäuren der allgemeinen Formel III um, in der R₄, R₅ und R₆ die oben genannten Bedeutungen haben und Y die Hydroxy­gruppe, ein Halogenid wie Chlorid oder Bromid, eine Alkyoxy- oder Aryloxygruppe, eine Alkylcarbonyloxy- oder eine Aryl­carbonyloxygruppe bedeutet (Schema 1):

Figure imgb0003
The compounds of general formula I according to the invention can be prepared by methods known per se. The synthesis from anilines and benzoic acids, as shown in Scheme 1 and Scheme 2, is particularly advantageous. For compounds of the general formula I in which A is the amino group -NH- and B is the carbonyl group -CO- (= general formula Ia), the anilines of the general formula II are used, in which R₁, R₂, R₃ and X are the above have meanings mentioned, with the benzoic acids of the general formula III in which R₄, R₅ and R₆ have the meanings given above and Y is the hydroxyl group, a halide such as chloride or bromide, an alkoxy or aryloxy group, an alkylcarbonyloxy or an arylcarbonyloxy group (Scheme 1):
Figure imgb0003

Für Verbindungen der allgemeinen Formel I, in der A die Carbonylgruppe -CO- und B die Aminogruppe -NH- bedeutet (= allgemeine Formel Ib), setzt man die Benzoesäuren der all­gemeinen Formel IV, in der R₁, R₂, R₃, X und Y die oben angege­benen Bedeutungen haben, mit den Anilinen der allgemeinen Formel V um, in der R₄, R₅ und R₆ die oben angegebenen Be­deutungen haben (Schema 2).

Figure imgb0004
For compounds of the general formula I in which A is the carbonyl group -CO- and B is the amino group -NH- (= general formula Ib), the benzoic acids of the general formula IV are used, in which R₁, R₂, R₃, X and Y. have the meanings given above, with the anilines of the general formula V in which R₄, R₅ and R₆ have the meanings given above (Scheme 2).
Figure imgb0004

Einen Überblick über die Verfahren zur Herstellung von Ver­bindungen der allgemeinen Formel I benutzten Methoden geben D. Döpp und H. Döpp in J. Falbe (Herausgeber), Methoden der Organischen Chemie (Houben-Weyl), Verlag Thieme, Stuttgart, New York, 1985, S. 934 ff.D. Döpp and H. Döpp in J. Falbe (Editor), Methods of Organic Chemistry (Houben-Weyl), Verlag Thieme, Stuttgart, New York, 1985 provide an overview of the methods used to prepare compounds of the general formula I , P. 934 ff.

Bedeutet in der allgemeinen Formel III oder IV Y die Hydroxy­gruppe, so sind die Verbindung der allgemeinen Formel III oder IV Carbonsäuren. Die bevorzugte Methode zur Umsetzung mit den Aminen, der allgemeinen Formel II oder V besteht in der Reaktion von etwa äquimolaren Mengen des Amins und der Säure in Gegenwart eines wasserentziehenden Mittels. Dafür kommt bei­spielsweise Polyphosphorsäure in Betracht, die dann gleich­zeitig als Lösungsmittel dient. Die Reaktionen laufen zwischen 50°C und 200°C ab. Die Endprodukte der allgemeinen Formel I fallen im allgemeinen nach Zugabe von Wasser aus und werden nach Filtration durch Umkristallisation oder säulenchromato­graphisch gereinigt. Eine weitere bevorzugte Methode zur Her­stellung von Verbindungen der allgemeinen Formel I besteht in der Umsetzung von etwa äquimolaren Mengen des Amins und der Säure in einem geeigneten Lösungsmittel mit etwa einer äquivalenten Menge eines Halogenierungsmittels, wie Phosphor­trichlorid, Phosphorpentachlorid oder Thionylchlorid, bei Tem­peraturen zwischen Raumtemperatur und der Rückflußtemperatur der Mischung. Geeignete Lösungsmittel sind Methylenchlorid Tetrachlorkohlenstoff, Diethylether, Toluol, Xylol oder Chlor­benzol. Im allgemeinen fällt das Produkt aus der Lösung aus und wird durch Filtration gewonnen. Falls erforderlich, kann die Reaktionsmischung konzentriert werden, bis zu einem Punkt, bei dem das Produkt aus der Lösung auszufallen beginnt. Als weitere Kondensationsmittel bei dieser Reaktion kommen saure Kationen­austauscher, Sulfoniumsalze, Schwefelsäurehalogenide, 2-­Halogenpyridiniumsalze, Phosphoniumsalze und Dicyclohexyl­carbodiimid in Betracht.If the hydroxy group in the general formula III or IV is Y, the compound of the general formula III or IV are carboxylic acids. The preferred method of reaction with the amines, general formula II or V, is to react approximately equimolar amounts of the amine and the acid in the presence of a dehydrating agent. For example, polyphosphoric acid comes into consideration, which then also serves as a solvent. The reactions take place between 50 ° C and 200 ° C. The end products of the general formula I generally precipitate out after the addition of water and are purified by filtration by recrystallization or by column chromatography. Another preferred method for the preparation of compounds of general formula I consists in reacting approximately equimolar amounts of the amine and the acid in a suitable solvent with approximately an equivalent amount of a halogenating agent, such as phosphorus trichloride, phosphorus pentachloride or thionyl chloride, at temperatures between room temperature and Reflux temperature of the mixture. Suitable solvents are methylene chloride Carbon tetrachloride, diethyl ether, toluene, xylene or chlorobenzene. In general, the product precipitates out of the solution and is obtained by filtration. If necessary, the reaction mixture can be concentrated to a point where the product begins to precipitate out of solution. Acidic cation exchangers, sulfonium salts, sulfuric acid halides, 2-halopyridinium salts, phosphonium salts and dicyclohexylcarbodiimide are suitable as further condensing agents in this reaction.

Bedeutet in der allgemeinen Formel III oder IV Y eine Alkoxy- oder Aryloxygruppe, so handelt es sich bei den Verbindungen der allgemeinen Formel III oder IV um Carbonsäureester. Man arbeitet in Gegenwart oder Abwesenheit spezieller Lösungsmittel bei Temperaturen im Bereich von 20°C bis zur Siedehitze des Gemisches. Bevorzugt ist dabei die Reaktion etwa äquimolarer Mengen des Amins und des Esters in Polyphosphorsäure bei 50°C - 200°C, jedoch kann man auch in einem inerten Lösungsmittel wie Methylenchlorid, Benzol, Toluol, Chlorbenzol am besten in Gegenwart von etwas mehr als einem Äquivalent einer Base wie Natriumethanolat oder Butyllithium, oder von Natriumhydrid in Dimethylsulfoxid arbeiten.If in the general formula III or IV Y denotes an alkoxy or aryloxy group, the compounds of the general formula III or IV are carboxylic acid esters. One works in the presence or absence of special solvents at temperatures in the range from 20 ° C to the boiling point of the mixture. The reaction of approximately equimolar amounts of the amine and the ester in polyphosphoric acid at 50 ° C. to 200 ° C. is preferred, but it is also best in an inert solvent such as methylene chloride, benzene, toluene, chlorobenzene in the presence of a little more than one equivalent a base such as sodium ethanolate or butyllithium, or sodium hydride in dimethyl sulfoxide.

Bedeutet in der allgemeinen Formel III oder IV Y eine Alkyl­carbonyloxy- oder Arylcarbonyloxygruppe, so handelt es sich bei den Verbindungen der allgemeinen Formel III oder IV um Anhydride. Da Anhydride im allgemeinen reaktiver sind als Carbonsäuren oder Carbonsäureester, kann man die Umsetzung mit den Aminen der allgemeinen Formel II oder V schon bei etwas niedrigeren Temperaturen vornehmen. Bevorzugt arbeitet man in einem inerten Lösungsmittel wie Dichlormethan, Diethylether, Benzol, Toluol, bei Temperaturen zwischen Raumtemperatur und 60°C. Man gibt dabei das Amin und das Anhydrid in etwa äqui­molaren Mengen zusammen, wobei im allgemeinen eine exotherme Reaktion einsetzt. Nach Abklingen wird zur Vervollständigung der Reaktion noch einige Zeit gelinde erwärmt.If in the general formula III or IV Y denotes an alkylcarbonyloxy or arylcarbonyloxy group, the compounds of the general formula III or IV are anhydrides. Since anhydrides are generally more reactive than carboxylic acids or carboxylic acid esters, the reaction with the amines of the general formula II or V can be carried out at somewhat lower temperatures. Is preferably carried out in an inert solvent such as dichloromethane, diethyl ether, benzene, toluene, at temperatures between room temperature and 60 ° C. The amine and the anhydride are combined in approximately equimolar amounts, an exothermic reaction generally starting. After the reaction has subsided, it is gently warmed for a while to complete the reaction.

Bedeutet in der allgemeinen Formel III oder IV Y ein Halogenid, so handelt es sich bei den Verbindungen der allgemeinen Formel III oder IV um Carbonsäurehalogenide. Darunter versteht man in erster Linie Säurechloride und -bromide. Da die Säurehalogenide reaktiver sind als die Carbonsäuren, -ester, oder -anhydride, ist es meist notwendig, die Reaktionsmischung zu kühlen. Man arbeitet am besten bei Temperaturen zwischen -10°C und Raum­temperatur.If in the general formula III or IV Y is a halide, the compounds of the general formula III or IV are carboxylic acid halides. This primarily means acid chlorides and bromides. Since the acid halides are more reactive than the carboxylic acids, esters or anhydrides, it is usually necessary to cool the reaction mixture. It is best to work at temperatures between -10 ° C and room temperature.

Bevorzugt geht man dabei so vor, daß nach Schotten-Baumann zur wässrigen Lösung des Amins der allgemeinen Formel II oder V, welche noch eine Base wie Alkalihydroxide, Natriumcarbonat oder Pyridin enthält, das Säurechlorid unter Eiskühlung langsam zutropft, und anschließend noch einige Zeit bei Raumtemperatur stehen läßt. Diese Reaktion ist nicht nur in Wasser möglich, sondern auch in organischen Lösungsmitteln wie Methylenchlorid, Ether, Benzol oder Toluol. Auch ohne säurebindende Mittel lassen sich die Amine durch Carbonsäurechloride nahezu quantitativ acylieren, in dem man das Amin und das Carbonsäure­chlorid in einem interten Lösungsmittel wie Methylenchlorid, Benzol oder Toluol bis zur Beendigung der Gasentwicklung kocht, was 1-24 Stunden dauert. Gibt man jedoch ein säurebindendes Mittel wie Triethylamin oder Pyridin in geringem Überschuß zu, so läuft die Reaktion schon bei Temperaturen zwischen -10°C und Raumtemperatur ab.The preferred procedure is that, according to Schotten-Baumann, the acid chloride is slowly added dropwise to the aqueous solution of the amine of the general formula II or V, which also contains a base such as alkali metal hydroxides, sodium carbonate or pyridine, and then cooled for some time at room temperature lets stand. This reaction is possible not only in water, but also in organic solvents such as methylene chloride, ether, benzene or toluene. Even without acid-binding agents, the amines can be acylated almost quantitatively by carboxylic acid chlorides by boiling the amine and the carboxylic acid chloride in an inert solvent such as methylene chloride, benzene or toluene until the evolution of gas has ended, which takes 1-24 hours. However, if an acid-binding agent such as triethylamine or pyridine is added in a slight excess, the reaction takes place at temperatures between -10 ° C. and room temperature.

Verbindungen der allgemeinen Formel I können auch in andere Verbindungen der allgemeinen Formel I umgewandelt werden. Dies trifft zu für

  • a) für die Alkylierung von Verbindungen der allgemeinen Formel I, in der einer oder mehrere der Substituenten R₁, R₂, R₃ eine Hydroxy- oder Mercaptogruppe bedeutet, zu den entsprechenden Alkoxy- oder Alkylthioverbindungen. Diese Reaktionen werden vorzugsweise in einem Lösungsmittel wie Aceton, Ether, Benzol, Toluol oder Dimethylformamid bei Temperaturen zwischen -30°C und +100°C, vorzugsweise bei Raumtemperatur in Gegenwart einer Base wie Kaliumhydroxid und eines Alkylierungsmittels wie Alkylhalogeniden oder Alkylsulfaten durchgeführt,
  • b) für die Herstellung von Verbindungen der allgemeinen Formel I, in der R₁ eine Alkylsulfinyl- oder Alky­sulfonylgruppe darstellt, durch nachträgliche Oxidation einer Verbindung in der R₁ eine Alkylmercaptogruppe ist. Die Oxidation wird vorzugsweise in einem Lösungsmittel oder Lösungsmittelgemisch, z.B. Wasser, Wasser/Pyridin, Aceton, Eisessig, verdünnter Schwefelsäure oder Tri­fluoressigsäure, je nach dem verwendeten Oxidationsmittel zweckmäßigerweise bei Temperaturen zwischen -80°C und 100°C durchgeführt.
    Zur Herstellung einer Alkylsulfinylverbindung der all­gemeinen Formel I wird die Oxidation zweckmäßigerweise mit einem Aequivalent des verwendeten Oxidationsmittels durch­geführt, z.B. mit Wasserstoffperoxid in Eisessig, Tri­fluoressigsäure oder Ameisensäure bei 0 bis 20°C oder in Aceton bei 0 bis 60°C, mit einer Persäure wie Per­ameisensäure in Eisessig oder Trifluoressigsäure bei 0 bis 50°C oder mit m-Chlorperbenzoesäure in Methylenchlorid oder Chloroform bei -20 bis 60°C, mit Natriummetaperjodat in wässrigem Methanol oder Ethanol bei -15 bis 25°C, mit Brom in Eisessig oder wässriger Essigsäure, mit N-Bromid­succinimid in Ethanol, mit tert.-Butyl-hypochlorit in Methanol bei -80 bis -30°C, mit Jodbenzodichlorid in wässrigem Pyridin bei 0 bis 50°C, mit Salpetersäure in Eisessig bei 0 bis 20°C, mit Chromsäure in Eisessig oder in Aceton bei 0 bis 20°C und mit Sulfurylchlorid in Methylenchlorid bei -70°C, der hierbei erhaltene Thio­ether-Chlorkomplex wird zweckmäßigerweise mit wässrigem Ethanol hydrolysiert.
    Zur Herstellung einer Alkylsulfonylverbindung der all­gemeinen Formel I wird die Oxidation zweckmäßigerweise mit einem bzw. mit zwei oder mehr Aequivalenten des ver­wendeten Oxidationsmittels durchgeführt, z.B. Wasser­stoffperoxid in Eisessig, Trifluoressigsäure oder in Ameisensäure bei 20 bis 100°C oder in Aceton bei 0 bis 60°C,. mit einer Persäure wie Perameisensäure oder m-­Chlorperbenzoesäure in Eisessig, Trifluoressigsäure, Methylenchlorid oder Chloroform bei Temperaturen zwischen 0 und 60°C, mit Salpetersäure in Eisessig bei 0 bis 20°C, mit Chromsäure oder Kaliumpermanganat in Eisessig, Wasser/Schwefelsäure oder in Aceton bei 0 bis 20°C.
  • c) für die Herstellung von Verbindungen der allgemeinen Formel I, in der R₁ eine Alkansulfonyloxy-, Trifluor­methansulfonyloxy-, Alkansulfonylamino- oder Trifluor­methansulfonylaminogruppe darstellt, durch die nach­trägliche Umsetzung einer Verbindung in der R₁ eine Hydroxygruppe mit einer Sulfonsäure der allgemeinen Formel VI
    R₇-SO₃H      (VI),
    in der R₇ eine Alkyl- oder eine Trifluormethylgruppe dar­stellt, in Gegenwart eines wasserentziehenden und/oder die Säure oder das Amin aktivierenden Mittels oder mit deren reaktionsfähigen Derivaten.
    Die Umsetzung wird zweckmäßigerweise in einem Lösungs­mittel oder Lösungsmittelgemisch wie Methylenchlorid, Ether, Tetrahydrofuran, Dioxan oder Benzol gegebenenfalls in Gegenwart eines säurebindenden Mittels wie Natrium­carbonat, Triethylamin oder Pyridin, wobei die beiden letzteren gleichzeitig auch als Lösungsmittel verwendet werden können, in Gegenwart eines die Säure aktivierenden oder wasserentziehenden Mittels wie Thionylchlorid oder Phosphorpentachlorid, vorzugsweise jedoch mit einem reaktionsfähigen Derivat einer Verbindung der allgemeinen Formel VII z.B. mit deren Anhydrid oder Halogenid wie Methansulfonsäurechlorid oder Ethansulfonsäurechlorid, vorzugsweise bei Temperaturen zwischen 0 und 100°C, z.B. bei Temperaturen zwischen Raumtemperatur und 50°C, durch­geführt.
  • d) für die Herstellung von Verbindungen der allgemeinen Formel I, in der R₁ eine durch eine Amino-, Alkylamino- oder Dialkylaminogruppe substituierte Formylgruppe dar­stellt, durch die nachträgliche Umsetzung einer Verbindung in der R₁ eine Carboxylgruppe darstellt, oder einem reaktionsfähigen Derivat hiervon wie z.B. Ester oder Säurechlorid mit einem Amin der allgemeinen Formel VII
    Figure imgb0005
     in der R₈ und R₉, die gleich oder verschieden sein können, Wasserstoffatome oder Alkylgruppen darstellen, oder mit einem reaktionsfähigen Derivat hiervon, falls R₁ die Carboxylgruppe darstellt. Die Umsetzung wird zweckmäßiger­weise in einem Lösungsmittel wie Methylenchlorid, Ethanol, Chloroform, Tetrachlorkohlenstoff, Ether, Tetrahydrofuran, Dioxan, Benzol, Toluol, Acetonitril oder Dimethylformamid, gegebenenfalls in Gegenwart eines die Säure aktivierenden Mittels oder eines wasserentziehenden Mittels, z.B. in Gegenwart von Chlorameisensäureethylester, Thionylchlorid, Phosphortrichlorid, Phosphorpentoxid, N,N′-Dicyclohexyl­carbodiimid/N-Hydroxysuccinimid, N,N′-Carbonyldiimidazol oder N,N′-Thionyldiimidazol oder Triphenylphosphin/Tetra­ chlorkohlenstoff, oder eines die Aminogruppe aktivierenden Mittels, z.B. Phosphortrichlorid, und gegebenenfalls in Gegenwart einer anorganischen Base wie Natriumcarbonat oder einer tertiaeren organischen Base wie Triethylamin oder Pyridin, welche gleichzeitig als Lösungsmittel dienen können, bei Temperaturen zwischen -25 und 250°C, vorzugs­weise jedoch bei Temperaturen zwischen -10°C und der Siedetemperatur des verwendeten Lösungsmittels durchge­führt, desweiteren kann während der Umsetzung entstehendes Wasser durch azeotrope Destillation, z.B. durch Erhitzen mit Toluol am Wasserabscheider, oder durch Zugabe eines Trockenmittels wie Magnesiumsulfat oder Molekularsieb abgetrennt werden.
    Besonders vorteilhaft wird jedoch die Umsetzung mit einem entsprechenden Halogenid, z.B. dem Carbonsäure-chlorid und einem entsprechenden Amin, wobei dieses gleichzeitig als Lösungsmittel dienen kann, und bei Temperaturen zwischen 0 und 50°C durchgeführt.
  • e) die Verseifung von Verbindungen der allgemeinen Formel I, in der R₁ oder R₄ eine Cyanogruppe bedeutet, zu Ver­bindungen der allgemeinen Formel I, in der R₁ oder R₄ die Aminocarbonylgruppe bedeuten. Man arbeitet in Gegenwart einer Säure wie Salzsäure, Schwefelsäure, Phosphorsäure oder Trichloressigsäure, oder in Gegenwart einer Base wie Natriumhydroxid oder Kaliumhydroxid in einem geeigneten Lösungsmittel wie Wasser, Methanol, Wasser/Methanol, Wasser/Ethanol, Ethanol, Wasser/Isopropanol oder Wasser/Dioxan bei Temperaturen zwischen Raumtemperatur und der Siedetemperatur des Reaktionsgemisches, oder in einem inerten Lösungsmittel wie Dichlormethan unter Zusatz eines Phasentransfer-Katalysators wie Tetrabutylammoniumhydro­gensulfat, unter Zusatz von Wasserstoffperoxid, wobei man bei Raumtemperatur arbeiten kann,
  • f) die Reduktion von Verbindungen der allgemeinen Formel I, in der einer der Substituenten R₁, R₂ oder R₃ eine Nitro­gruppe bedeutet, zu Verbindungen der allgemeinen Formel I, in der R₁, R₂ oder R₃ eine Aminogruppe bedeuten. Die Hydrierung wird vorzugsweise in einem Lösungsmittel wie Wasser, Ethanol, Eiessig, Essigester oder Dimethylformamid mit Wasserstoff in Gegenwart eines Katalysators wie Raney-­Nickel, Platin oder Palladium/Kohle, mit Metallen wie Eisen, Zinn, oder Zink in Gegenwart einer Säure, mit Salzen wie Eisen(II)sulfat, Zinn(II)chlorid, Natrium­sulfid, Natriumhydrogensulfid oder Natriumdithionit, oder mit Hydrazin in Gegenwart von Raney-Nickel bei Tempera­turen zwischen 0 und 250°C, vorzugsweise jedoch bei Raum­temperatur, durchgeführt.
  • g) die Hydrierung einer Verbindung der allgemeinen Formel I, in der X die Vinylengruppe bedeutet, zu Verbindungen der allgemeinen Formel I, in der X die Ethylengruppe be­deutet.
    Die Hydrierung wird vorzugsweise in einem Lösungsmittel wie Wasser, Wasser/Ethanol, Methanol, Eisessig, Essig­ester, Dimethylformamid, in Gegenwart von Wasserstoff und einem Katalysator wie Raney-Nickel, Platin oder Palladium/Kohle durchgeführt.
  • h) die Reduktion von Verbindungen der allgemeinen Formel I, in der R₄ eine Cyanogruppe bedeutet, zu Verbindungen der allgemeinen Formel I, in der R₄ eine Aminomethylgruppe bedeutet. Diese Reduktion führt man mit Wasserstoff unter Druck in Gegenwart von Ammoniak und einem Katalysator wie Raney-Nickel durch, vorzugsweise bei Temperaturen zwischen 50°C und 150°C und Drücken von 50-250 bar.
  • i) die Reduktion einer Verbindung der allgemeinen Formel I, in der einer der Substituenten R₁, R₂ oder R₃ eine Alkyl­oxycarbonylgruppe enthält zur entsprechenden Hydroxyalkyl­verbindung. Diese Reduktion führt man vorzugsweise mit Lithiumaluminiumhydrid in einem Ether wie Diethylether oder Dioxan am Siedepunkt des Lösungsmittels durch.
  • j) die Verseifung einer Verbindung der allgemeinen Formel I, in der einer der Substituenten R₁, R₂ oder R₃ eine Alkoxy­carbonylgruppe enthält zur entsprechenden Hydroxycarbonyl­verbindung. Solche Verseifungen führt man vorzugsweise in wässriger oder wässrig-alkoholischer Natronlauge oder Kaliumhydroxidlösung durch, und setzt dann die Säure durch Ansäuern mit einer Mineralsäure frei.
  • k) die Nitrierung von Verbindungen der allgemeinen Formel I, in der X eine Bindung darstellt, A eine Aminogruppe -NH- und B die Carbonylgruppe -CO-. Dabei entstehen Ver­bindungen, in der einer der Substituenten R₁, R₂ oder R₃ die Nitrogruppe darstellt, die in ortho-Stellung zur Amid­funktion A-B (= -NH-CO-) eintritt.
Compounds of the general formula I can also be converted into other compounds of the general formula I. This is true for
  • a) for the alkylation of compounds of general formula I, in which one or more of the substituents R₁, R₂, R₃ is a hydroxyl or mercapto group, to the corresponding alkoxy or alkylthio compounds. These reactions are preferably carried out in a solvent such as Acetone, ether, benzene, toluene or dimethylformamide at temperatures between -30 ° C and + 100 ° C, preferably at room temperature in the presence of a base such as potassium hydroxide and an alkylating agent such as alkyl halides or alkyl sulfates,
  • b) for the preparation of compounds of general formula I, in which R₁ represents an alkylsulfinyl or alkysulfonyl group, by subsequent oxidation of a compound in which R₁ is an alkyl mercapto group. The oxidation is preferably carried out in a solvent or solvent mixture, for example water, water / pyridine, acetone, glacial acetic acid, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used, advantageously at temperatures between -80 ° C. and 100 ° C.
    To prepare an alkylsulfinyl compound of the general formula I, the oxidation is advantageously carried out with one equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C. or in acetone at 0 to 60 ° C., with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20 to 60 ° C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25 ° C, with bromine in glacial acetic acid or aqueous acetic acid, with N-bromide succinimide in ethanol, with tert-butyl hypochlorite in methanol at -80 to -30 ° C, with iodobenzodichloride in aqueous pyridine at 0 to 50 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid in glacial acetic acid or in acetone at 0 to 20 ° C and with sulfuryl chloride in methylene chloride at -70 ° C, the thioether-chlorine complex obtained is advantageously ise hydrolyzed with aqueous ethanol.
    To prepare an alkylsulfonyl compound of the general formula I, the oxidation is advantageously carried out using one or two or more equivalents of the oxidizing agent used, for example hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20 to 100 ° C. or in acetone at 0 to 60 ° C. ,. with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid or potassium permanganate in glacial acetic acid, water / sulfuric acid or in acetone at 0 to 20 ° C.
  • c) for the preparation of compounds of general formula I, in which R₁ represents an alkanesulfonyloxy, trifluoromethanesulfonyloxy, alkanesulfonylamino or trifluoromethanesulfonylamino group, by the subsequent reaction of a compound in which R₁ represents a hydroxy group with a sulfonic acid of the general formula VI
    R₇-SO₃H (VI),
    in which R₇ represents an alkyl or a trifluoromethyl group, in the presence of a dehydrating agent and / or the acid or the amine-activating agent or with their reactive derivatives.
    The reaction is advantageously carried out in a solvent or solvent mixture such as methylene chloride, ether, tetrahydrofuran, dioxane or benzene, optionally in the presence of an acid-binding agent such as sodium carbonate, triethylamine or pyridine, the two the latter can also be used as a solvent, in the presence of an acid-activating or dehydrating agent such as thionyl chloride or phosphorus pentachloride, but preferably with a reactive derivative of a compound of general formula VII, for example with its anhydride or halide such as methanesulfonyl chloride or ethanesulfonyl chloride, preferably at temperatures between 0 and 100 ° C, for example at temperatures between room temperature and 50 ° C, carried out.
  • d) for the preparation of compounds of general formula I in which R₁ represents a substituted by an amino, alkylamino or dialkylamino group, by the subsequent reaction of a compound in the R₁ represents a carboxyl group, or a reactive derivative thereof such as esters or acid chloride with an amine of the general formula VII
    Figure imgb0005
     in which R₈ and R₉, which may be the same or different, represent hydrogen atoms or alkyl groups, or with a reactive derivative thereof, if R₁ represents the carboxyl group. The reaction is advantageously carried out in a solvent such as methylene chloride, ethanol, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of ethyl chloroformate, thionyl chloride , Phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / tetra chlorinated carbon, or an agent activating the amino group, for example phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which can simultaneously serve as a solvent, at temperatures between -25 and 250 ° C., but preferably carried out at temperatures between -10 ° C and the boiling point of the solvent used, furthermore, water formed during the reaction can be separated off by azeotropic distillation, for example by heating with toluene on a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieve.
    However, the reaction with a corresponding halide, for example the carboxylic acid chloride and a corresponding amine, which can simultaneously serve as a solvent, and is carried out at temperatures between 0 and 50 ° C. is particularly advantageous.
  • e) the saponification of compounds of the general formula I in which R₁ or R₄ is a cyano group, to compounds of the general formula I in which R₁ or R₄ is the aminocarbonyl group. One works in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid, or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, water / methanol, water / ethanol, ethanol, water / isopropanol or water / dioxane at temperatures between room temperature and the boiling point of the reaction mixture, or in an inert solvent such as dichloromethane with the addition of a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate, with the addition of hydrogen peroxide, it being possible to work at room temperature,
  • f) the reduction of compounds of general formula I in which one of the substituents R₁, R₂ or R₃ represents a nitro group, to compounds of general formula I in which R₁, R₂ or R₃ represent an amino group. The hydrogenation is preferably carried out in a solvent such as water, ethanol, vinegar, ethyl acetate or dimethylformamide with hydrogen in the presence of a catalyst such as Raney nickel, platinum or palladium / carbon, with metals such as iron, tin, or zinc in the presence of an acid, with salts such as iron (II) sulfate, tin (II) chloride, sodium sulfide, sodium hydrogen sulfide or sodium dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 250 ° C, but preferably at room temperature.
  • g) the hydrogenation of a compound of the general formula I in which X represents the vinylene group to give compounds of general formula I in which X represents the ethylene group.
    The hydrogenation is preferably carried out in a solvent such as water, water / ethanol, methanol, glacial acetic acid, ethyl acetate, dimethylformamide, in the presence of hydrogen and a catalyst such as Raney nickel, platinum or palladium / carbon.
  • h) the reduction of compounds of general formula I, in which R₄ represents a cyano group, to compounds of general formula I, in which R₄ represents an aminomethyl group. This reduction is carried out with hydrogen under pressure in the presence of ammonia and a catalyst such as Raney nickel, preferably at temperatures between 50 ° C. and 150 ° C. and pressures of 50-250 bar.
  • i) the reduction of a compound of general formula I in which one of the substituents R₁, R₂ or R₃ contains an alkyloxycarbonyl group to give the corresponding hydroxyalkyl compound. This reduction is preferably carried out with lithium aluminum hydride in an ether such as diethyl ether or dioxane at the boiling point of the solvent.
  • j) the saponification of a compound of the general formula I in which one of the substituents R₁, R₂ or R₃ contains an alkoxycarbonyl group to give the corresponding hydroxycarbonyl compound. Such saponifications are preferably carried out in aqueous or aqueous-alcoholic sodium hydroxide solution or potassium hydroxide solution, and the acid is then released by acidification with a mineral acid.
  • k) the nitration of compounds of general formula I, in which X represents a bond, A an amino group -NH- and B the carbonyl group -CO-. This creates compounds in which one of the substituents R₁, R₂ or R₃ represents the nitro group which occurs in the ortho position to the amide function AB (= -NH-CO-).

Die Nitrierung führt man bevorzugt mit Salpetersäure in Schwefelsäure bei Temperaturen zwischen -20°C und +50°C durch. Sie kann jedoch auch ohne Schwefelsäure, oder an deren Stelle in Wasser, Eisessig oder Acetanhydrid durchgeführt werden, oder mit N₂O₅ in CCl₄ in Gegenwart von P₂O₅. Als Nitrierungs­reagenzien können auch Anhydride wie Acetylnitrat, oder Nitryl­halogenide mit FeCl₃, Methylnitrat und BF₃, oder Nitroniumsalze wie NO₂BF₄, NO₂PF₆ oder NO₂CF₃SO₃ dienen. Zur Nitrierung kann auch eine Mischung aus Salpetersäure und salpetriger Säure benutzt werden, welche N₂O₄ als eigentliche nitrierende Spezies liefert.The nitration is preferably carried out with nitric acid in sulfuric acid at temperatures between -20 ° C and + 50 ° C. However, it can also be carried out without sulfuric acid, or in its place in water, glacial acetic acid or acetic anhydride, or with N₂O₅ in CCl₄ in the presence of P₂O₅. Anhydrides such as acetyl nitrate or nitryl halides with FeCl₃, methyl nitrate and BF₃, or nitronium salts such as NO₂BF₄, NO₂PF₆ or NO₂CF₃SO₃ can also serve as nitrating reagents. A mixture of nitric acid and nitrous acid can also be used for nitration, which provides N₂O₄ as the actual nitrating species.

Die als Vorstufen zur Herstellung von Verbindungen der all­gemeinen Formel I gemäß Schema 1 und Schema 2 benötigten Aniline der allgemeinen Formel II und der Benzoesäure der all­gemeinen Formel IV sind käuflich oder literaturbekannt. Von den Anilinen der allgemeinen Formel V ist 4-tert.Butylanilin käuf­lich, die anderen sind literaturbekannt (vgl. Jönsson, Acta chem. scand. 8 (1954) 1211; Nerdel, Würgau, Liebigs Ann. Chem. 621 (1959) 34), oder können nach den darin beschriebenen Methoden hergestellt werden.

Figure imgb0006
The anilines of the general formula II and the benzoic acid of the general formula IV required as precursors for the preparation of compounds of the general formula I according to Scheme 1 and Scheme 2 are commercially available or known from the literature. 4-tert-butylaniline of the anilines of the general formula V is commercially available, the others are known from the literature (cf. Jönsson, Acta chem. Scand. 8 (1954) 1211; Nerdel, Würgau, Liebigs Ann. Chem. 621 (1959) 34) , or can be prepared according to the methods described therein.
Figure imgb0006

Verbindungen der allgemeinen Formel III, in der R₄ die Cyano­gruppe bedeutet, R₅ und R₆ die oben angegebenen Bedeutungen haben und Y die Alkoxygruppe bedeutet (= allgemeine Formeln III a und III b) stellt man durch schrittweise Alkylierung von 4-­(Cyanomethyl)benzoesäureestern her, z.B. der Verbindung VIII, mit den Alkylierungsmitteln der allgemeinen Formeln IX und X, in denen Alkyl eine C₁-C₆-Alkylgruppe oder eine C₃-C₆-Cyclo­alkylgruppe bedeutet und Hal ein Halogenatom, vorzugsweise Chlorid oder Bromid bedeutet. Die Verbindungen der allgemeinen Formeln IX oder X können gleich oder verschieden sein. Bilden in der allgemeinen Formel III R₅ und R₆ zusammen mit dem C-­Atom, an das sie gebunden sind, einen Cycloalkylring und R₄ die Cyanogruppe und Y die Alkoxygruppe (= allgemeinen Formel III c), so führt man die Alkylierung der Verbindung VIII mit dem Alkylendihalogenid der allgemeinen Formel XI durch:

Figure imgb0007
Compounds of the general formula III, in which R₄ is cyano, R₅ and R₆ have the meanings given above and Y is alkoxy (= general formulas III a and III b) are prepared by stepwise alkylation of 4- (cyanomethyl) benzoic esters, for example the compound VIII, with the alkylating agents of the general formulas IX and X, in which alkyl is a C₁-C₆-alkyl group or a C₃-C₆-cycloalkyl group and Hal is a halogen atom, preferably chloride or bromide. The compounds of the general formulas IX or X can be the same or different. In the general formula III, R₅ and R₆ together with the carbon atom to which they are attached form a cycloalkyl ring and R₄ the Cyano group and Y the alkoxy group (= general formula III c), the alkylation of compound VIII is carried out with the alkylene dihalide of the general formula XI:
Figure imgb0007

Diese Alkylierungen führt man in einem inerten Lösungsmittel wie Dichlormethan, Ether, Toluol, Xylol in Gegenwart einer Base wie Natronlauge oder Kalilauge, gewünschtenfalls in Gegenwart eines Phasentransfer-Katalysators wie Tetrabutylammoniumbromid und einem Äuivalent des Alkylierungsmittels IX, X oder XI, durch.These alkylations are carried out in an inert solvent such as dichloromethane, ether, toluene, xylene in the presence of a base such as sodium hydroxide solution or potassium hydroxide solution, if desired in the presence of a phase transfer catalyst such as tetrabutylammonium bromide and one equivalent of the alkylating agent IX, X or XI.

Die Verbindung VIII ist literaturbekannt: J.F.Codington, E. Mosettig, J.Org.Chem. 17 (1952), 1035.Compound VIII is known from the literature: JFCodington, E. Mosettig, J.Org.Chem. 17 (1952), 1035.

Ein weiteres Verfahren zur Herstellung von Verbindungen der allgemeinen Formel III geht aus von den Anilinen der allge­meinen Formel V

Figure imgb0008
Another process for the preparation of compounds of the general formula III is based on the anilines of the general formula V
Figure imgb0008

Durch die Reaktionsfolge Diazotierung, Cyanierung (Sandmeyer-­Reaktion) und Verseifung des Nitrils können die Verbindungen der allgemeinen Formel III gewonnen werden.The compounds of the general formula III can be obtained by the reaction sequence diazotization, cyanation (Sandmeyer reaction) and saponification of the nitrile.

Die Verbindungen der Formel I können auch Ausgangsverbindungen zur Herstellung von anderen pharmazeutisch wirksamen Verbindungen sein, die Gegenstand der deutschen Patentanmeldung P 3830060.5 sind.The compounds of the formula I can also be starting compounds for the preparation of other pharmaceutically active compounds which are the subject of German patent application P 3830060.5.

Zur Herstellung von Arzneimitteln werden die Substanzen der allgemeinen Formel I in an sich bekannter Weise mit geeigneten pharmazeutischen Trägersubstanzen, Aroma-, Geschmacks- und Farbstoffen gemischt und beispielsweise als Tabletten oder Dragees ausgeformt oder unter Zugabe entsprechender Hilfsstoffe in Wasser oder Öl, wie z.B. Olivenöl, suspendiert oder ge­löst.For the production of pharmaceuticals, the substances of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and are shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as e.g. Olive oil, suspended or dissolved.

Die Substanzen der allgemeinen Formel I und ihre Salze können in flüssiger oder fester Form enteral oder parenteral appli­ziert werden. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei Injektionslösungen üblichen Zusätze wie Stabilisierungs-mittel, Lösungsvermittler oder Puffer enthält.The substances of general formula I and their salts can be administered enterally or parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers or buffers.

Derartige Zusätze sind z.B. Tartrat- und Citratpuffer, Ethanol, Komplexbildner (wie Ethylendiamintetraessigsäure und deren nicht toxische Salze) und hochmolekulare Polymere (wie flüs­siges Polyethylenoxid) zur Viskositätsregulierung. Feste Trägerstoffe sind z.B. Stärke, Lactose, Mannit, Methylcellu­lose, Talkum, hochdisperse Kieselsäuren, hochmolekulare Fett­säuren (wie Staerinsäure), Gelatine, Agar-Agar, Calcium­phosphat, Magnesiumstearat, tierische und pflanzliche Fette und feste hochmolekulare Polymere (wie Polyethylenglykole). Für orale Applikation geeignete Zubereitungen können gewünschten­falls Geschmacks- und Süßstoffe enthalten.Such additives are e.g. Tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.

Die Verbindungen der Formel I können gewünschtenfalls in ihre physiologisch verträgliche Säureadditionssalze mit anorganischen oder organischen Säuren überführt werden. Als Säuren kommen beispielsweise Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Fumarsäure, Bernsteinsäure, Weinsäure, Zitronensäure, Milchsäure, Maleinsäure oder Methansulfonsäure in Betracht.If desired, the compounds of the formula I can be converted into their physiologically tolerable acid addition salts with inorganic or organic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.

Die Verbindungen werden üblicherweise in Mengen von 10-1500 mg pro Tag bezogen auf 75 kg Körpergewicht appliziert. Bevorzugt ist es, 2-3 mal pro Tag 1-2 Tabletten mit einem Wirkstoffgehalt von 5-500 mg zu verabreichen. Die Tabletten können auch re­tardiert sein, wodurch nur noch 1 mal pro Tag 1-2 Tabletten mit 20-700 mg Wirkstoff gegeben werden müssen. Der Wirkstoff kann auch durch Injektion 1-8 mal pro Tag bzw. durch Dauerinfusion gegeben werden, wobei Mengen von 10-1000 mg pro Tag normaler­weise ausreichen.The compounds are usually applied in amounts of 10-1500 mg per day based on 75 kg of body weight. It is preferred to administer 1-2 tablets with an active substance content of 5-500 mg 2-3 times a day. The tablets can also be delayed, which means that 1-2 tablets with 20-700 mg of active ingredient have to be given only once per day. The active ingredient can also be given by injection 1-8 times a day or by continuous infusion, with amounts of 10-1000 mg per day usually being sufficient.

Bevorzugt im Sinne der Erfindung sind außer den in den Bei­spielen genannten Verbindungen die folgenden:
N-(2-Hydroxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-(Methoxycarbonyl)phenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Ethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Mercaptophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Cyanophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-(Ethoxy)phenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-(sec.Butyl)phenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-(Hydroxymethyl)phenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Carboxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Ethoxycarbonyl)phenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Biphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Fluorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Bromphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Iodphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Acetylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Allyloxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Carboxylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Hydroxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Ethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Cyanophenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Hydroxymethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Acetylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Dimethylaminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Fluorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Iodphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Ethyloxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Bromphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Allyloxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Acetylaminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Acetylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Hydroxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Carboxymethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Ethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Aminocarbonylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Bromphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Ethyloxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-sec.Butylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Butylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Isopropylphenyl)-4-(1,1-dimethylethyl)benzamid
N-<4-[N′-Ethyl-N′-(2-hydroxyethyl)aminophenyl]>-4-(1,1-di­methylethyl)benzamid
N-(4-Propinylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Diethylaminophenyl-4-(1,1-dimethylethyl)benzamid
N-(4-Fluorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Iodphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Sulfonylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Carboxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Allyloxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Chlor-2-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methyl-3-nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methyl-3-aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(5,6,7,8-Tetrahydronaphthalin-1-yl)-4-(1,1-dimethyl­ethyl)benzamid
N-(2,3-Dichlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,3-Dimethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Hydroxy-2-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4-Dimethoxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Chlor-4-nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Chlor-4-aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Chlor-2-nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Chlor-2-aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Chlor-2-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4-Dinitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4-Diaminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Nitro-4-methoxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Amino-4-methoxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Nitro-2-methoxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Amino-2-methoxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Nitro-2-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Amino-2-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Hydroxy-4-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Brom-4-nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Brom-4-aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4-Dichlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4-Dimethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4-Difluorphenhyl-4-(1,1-dimethylethyl)benzamid
N-(4-Methyl-2-chlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,5-Dimethoxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Hydroxy-5-chlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methyl-5-chlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methoxy-5-nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methoxy-5-aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methyl-5-nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methyl-5-aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,5-Dimethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Nitro-5-chlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Amino-5-chlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methyl-5-fluorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,5-Bis(methoxycarbonyl)phenyl)-4-(1,1-dimethylethyl)­benzamid
N-(2,5-Dichlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Hydroxy-5-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,6-Dimethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,6-Dichlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methyl-6-nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Methyl-6-aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Chlor-4-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Methoxy-4-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3,4-Dimethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Nitro-4-fluorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3-Amino-4-fluorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(1,4-Benzodioxan-6-yl)-4-(1,1-dimethylethyl)benzamid
N-(3-Chlor-4-fluorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3,4-Dichlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3,5-Dimethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3,5-Dimethoxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4,5-Trichlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4,6-Trimethylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,6-Dichlor-4-nitrophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,6-Dichlor-4-aminophenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4,6-Trichlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2,4,6-Tribromphenyl)-4-(1,1-dimethylethyl)benzamid
N-(3,5-Dimethyl-4-hydroxyphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Allyloxy-2-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Allyloxy-4-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Allyloxy-5-chlorphenyl)-4-(1,1-dimethylethyl)benzamid
N-(2-Allyloxy-5-methylphenyl)-4-(1,1-dimethylethyl)benzamid
N-(4-Allyloxy-3,5-dimethylphenyl)-4-(1,1-dimethylethyl)­benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-(4-methoxyphenyl)benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-hydroxy-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-propyloxy-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-allyloxy-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-benzyloxy-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-methylsulfonyloxybenzamid
N-(4-(1,1-Dimethylethyl)phenyl)-2-methoy-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-3-methoxy-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-2-chlor-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-3-chlor-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-chlor-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-methylmercapto-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-methyl-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-cyano-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-nitro-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-dimethylamino-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-3,4-dimethoxy-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-3,4-methylendioxy-­benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-(3-pyridinyoxy-benzamid
N-(4-(1,1-Dimethylethyl)phenyl)-4-amino-benzamid
N-(4-(1-Cyano-cyclopentyl)phenyl)-4-methoxy-benzamid
N-(4-(1-Aminocarbonyl-cyclopentyl)phenyl)-4-methoxy-benzamid
N-(4-(1-Aminomethyl-cyclopentyl)phenyl)-4-methoxy-benzamidIn addition to the compounds mentioned in the examples, the following are preferred for the purposes of the invention:
N- (2-hydroxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2- (methoxycarbonyl) phenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-ethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-mercaptophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-cyanophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2- (ethoxy) phenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2- (sec-butyl) phenyl) -4- (1,1-dimethylethyl) benzamide
N- (2- (hydroxymethyl) phenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-carboxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-ethoxycarbonyl) phenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-biphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-fluorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-bromophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-iodophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-acetylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-allyloxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-carboxylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-hydroxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-ethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-cyanophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-hydroxymethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-acetylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-dimethylaminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-fluorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-iodophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-ethyloxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-bromophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-allyloxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-acetylaminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-acetylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-hydroxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-carboxymethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-ethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-aminocarbonylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-bromophenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-ethyloxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-sec-butylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-butylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-isopropylphenyl) -4- (1,1-dimethylethyl) benzamide
N- <4- [N'-ethyl-N '- (2-hydroxyethyl) aminophenyl]> - 4- (1,1-dimethylethyl) benzamide
N- (4-propynylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-diethylaminophenyl-4- (1,1-dimethylethyl) benzamide
N- (4-fluorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-iodophenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-sulfonylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-carboxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-allyloxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-chloro-2-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methyl-3-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methyl-3-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (5,6,7,8-tetrahydronaphthalin-1-yl) -4- (1,1-dimethylethyl) benzamide
N- (2,3-dichlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,3-dimethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-Hydroxy-2-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4-dimethoxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-chloro-4-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-chloro-4-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-chloro-2-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-chloro-2-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-chloro-2-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4-dinitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4-diaminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-nitro-4-methoxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-Amino-4-methoxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-nitro-2-methoxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-amino-2-methoxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-nitro-2-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-Amino-2-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-Hydroxy-4-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-bromo-4-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-bromo-4-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4-dichlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4-dimethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4-difluorophenyl-4- (1,1-dimethylethyl) benzamide
N- (4-methyl-2-chlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,5-dimethoxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-Hydroxy-5-chlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methyl-5-chlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methoxy-5-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methoxy-5-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methyl-5-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methyl-5-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,5-dimethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-nitro-5-chlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-amino-5-chlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methyl-5-fluorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,5-bis (methoxycarbonyl) phenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,5-dichlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-Hydroxy-5-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,6-dimethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,6-dichlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methyl-6-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-methyl-6-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-chloro-4-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-methoxy-4-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3,4-dimethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-nitro-4-fluorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3-amino-4-fluorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (1,4-Benzodioxan-6-yl) -4- (1,1-dimethylethyl) benzamide
N- (3-chloro-4-fluorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3,4-dichlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3,5-dimethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (3,5-dimethoxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4,5-trichlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4,6-trimethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,6-dichloro-4-nitrophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,6-dichloro-4-aminophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4,6-trichlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2,4,6-tribromophenyl) -4- (1,1-dimethylethyl) benzamide
N- (3,5-dimethyl-4-hydroxyphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-allyloxy-2-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-allyloxy-4-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-allyloxy-5-chlorophenyl) -4- (1,1-dimethylethyl) benzamide
N- (2-allyloxy-5-methylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4-allyloxy-3,5-dimethylphenyl) -4- (1,1-dimethylethyl) benzamide
N- (4- (1,1-Dimethylethyl) phenyl) - (4-methoxyphenyl) benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-hydroxy-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-propyloxy-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-allyloxy-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-benzyloxy-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-methylsulfonyloxybenzamide
N- (4- (1,1-Dimethylethyl) phenyl) -2-methoybenzamide
N- (4- (1,1-Dimethylethyl) phenyl) -3-methoxy-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -2-chloro-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -3-chlorobenzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-chloro-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-methylmercapto-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-methyl-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-cyano-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-nitro-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-dimethylamino-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -3,4-dimethoxy-benzamide
N- (4- (1,1-Dimethylethyl) phenyl) -3,4-methylenedioxybenzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4- (3-pyridinyoxybenzamide
N- (4- (1,1-Dimethylethyl) phenyl) -4-amino-benzamide
N- (4- (1-Cyano-cyclopentyl) phenyl) -4-methoxy-benzamide
N- (4- (1-aminocarbonylcyclopentyl) phenyl) -4-methoxy-benzamide
N- (4- (1-Aminomethyl-cyclopentyl) phenyl) -4-methoxy-benzamide

Beispiel 1example 1 4-(1,1-Dimethylethyl)-N-(4-methoxyphenyl)benzamid4- (1,1-dimethylethyl) -N- (4-methoxyphenyl) benzamide

Zu einer Lösung von 2.50 g (0.02 mol) 4-Methoxyanilin und 3 ml (0.22 mol) Triethylamin in 30 ml Dichlormethan tropfte man unter Eiskühlung und Feuchtigkeitsausschluß innerhalb 1 Stunde eine Lösung von 4.3 ml (0.22 mol) 4-(1,1-Dimethylethyl)-benzoe­säurechlorid in 40 ml Dichlormethan. Nach 30 min Rühren bei Raumtemperatur wurde das Lösungsmittel i. Vak. entfernt, der Rückstand mit Wasser digeriert und abgesaugt. Man erhielt 4.2 g Rohprodukt, daß man aus 150 ml Essigester umkristallisierte und bei 40°C i. Vak. trocknete:
3.0 g (53 %) farblose Kristalle mit dem Fp. 119-120°C.A solution of 4.3 ml (0.22 mol) of 4- (1,1-) was added dropwise to a solution of 2.50 g (0.02 mol) of 4-methoxyaniline and 3 ml (0.22 mol) of triethylamine in 30 ml of dichloromethane while cooling with ice and excluding moisture. Dimethylethyl) benzoic acid chloride in 40 ml dichloromethane. After stirring at room temperature for 30 min, the solvent was evaporated down i. Vac. removed, the residue digested with water and suction filtered. 4.2 g of crude product were obtained, which was recrystallized from 150 ml of ethyl acetate and at 40 ° C. i. Vac. dried:
3.0 g (53%) colorless crystals with mp 119-120 ° C.

Analog dem Beispiel 1 erhielt man durch Umsetzung der an­gegebenen Amine mit 4-(1,1-Dimethylethyl)benzoesäurechlorid die folgenden Verbindungen:

Figure imgb0009
Figure imgb0010
 Analogously to Example 1, the following compounds were obtained by reacting the specified amines with 4- (1,1-dimethylethyl) benzoic acid chloride:
Figure imgb0009
Figure imgb0010

Beispiel 20Example 20 N-(4-Aminophenyl)-4-(1,1-dimethylethyl)benzamidN- (4-aminophenyl) -4- (1,1-dimethylethyl) benzamide

4.5 g (0.015 mol) 4-(1,1-Dimethylethyl)-N-(4-nitrophenyl)benz­amid (Beispiel 15) hydrierte man bei Normaldruck und Raumtempe­ratur in Gegenwart von 0.5 g 10 % Palladium auf Kohle. Nach 30 min wurde filtriert und das Filtrat i.Vak. eingeengt. Der Rückstand wurde mit Ligroin digeriert und abgesaugt. Man erhielt 3.4 g (85 %) der Titelverbindung mit dem Fp. 111-­113°C.4.5 g (0.015 mol) of 4- (1,1-dimethylethyl) -N- (4-nitrophenyl) benzamide (Example 15) were hydrogenated at atmospheric pressure and room temperature in the presence of 0.5 g of 10% palladium on carbon. After 30 min the mixture was filtered and the filtrate i.Vac. constricted. The residue was digested with ligroin and suction filtered. 3.4 g (85%) of the title compound with mp 111-113 ° C. were obtained.

Beispiel 21Example 21 N-(4-Methoxyphenyl)-4-(1-cyanoethyl)benzamidN- (4-methoxyphenyl) -4- (1-cyanoethyl) benzamide

Analog dem Beispiel 1 setzte man 0.17 g 4-Methoxyanilin mit 0.3 g 4-(1-Cyanoethyl)benzoesäurechlorid um und erhielt nach Um­kristallisation aus Methanol 0.23 g (60 %) der Titelverbindung als cremefarbenes Pulver mit dem Fp. 176-178°C.Analogously to Example 1, 0.17 g of 4-methoxyaniline was reacted with 0.3 g of 4- (1-cyanoethyl) benzoic acid chloride and, after recrystallization from methanol, 0.23 g (60%) of the title compound was obtained as an off-white powder with a melting point of 176-178 ° C.

4-(1-Cyanoethyl)benzoesäurechlorid stellte man wie folgt her:
1.75 g (10 mmol) 4-(Cyanomethyl)benzoesäuremethylester (J.F. Codington et al., J.Org.Chem. 17 (1952) 1035) und 0.28 g Tetra­butylammoniumbromid in 9.7 ml 50 % Natronlauge versetzte man unter Eiskühlung mit 0.62 ml Iodmethan, gab nach 1 h Dichlor­methan und Eiswasser zu, trennte das Dichlormethan ab, wusch es mit Wasser neutral, trocknete und entfernte das Lösungsmittel i.Vak. Das zurückbleibende Öl reinigte man säulenchromato­graphisch (Kieselgel, n-Heptan/Methylethylketon = 6:1). Die entsprechenden Fraktionen wurden vereinigt und das Lösungs­mittel i.Vak. entfernte. Man erhielt 0.57 g (30 %) 4-(1-Cyano­ethyl)benzoesäuremethylester als Öl.4- (1-cyanoethyl) benzoic acid chloride was prepared as follows:
1.75 g (10 mmol) of methyl 4- (cyanomethyl) benzoate (JF Codington et al., J.Org.Chem. 17 (1952) 1035) and 0.28 g of tetrabutylammonium bromide in 9.7 ml of 50% sodium hydroxide solution were treated with 0.62 ml of iodomethane while cooling with ice. added dichloromethane and ice water after 1 h, separated off the dichloromethane, washed it with water until neutral, dried and removed the solvent in vacuo. The remaining oil was purified by column chromatography (silica gel, n-heptane / methyl ethyl ketone = 6: 1). The appropriate fractions were combined and the solvent i.Vac. removed. 0.57 g (30%) of methyl 4- (1-cyanoethyl) benzoate was obtained as an oil.

Diesen Ester rührte man 4 h in 5 ml Methanol und 1.7 ml 2 N Natronlauge, entfernte das Lösungsmittel i.Vak., säuerte mit 2 N HCl an, saugte den Niederschlag ab, wusch mit Wasser und trocknete. Man erhielt 0.32 g (69 %) 4-(1-Cyanoethyl)benzoe­säure mit dem Fp. 113-116°C.This ester was stirred for 4 h in 5 ml of methanol and 1.7 ml of 2N sodium hydroxide solution, the solvent was removed in vacuo, acidified with 2N HCl, the precipitate was filtered off, washed with water and dried. 0.32 g (69%) of 4- (1-cyanoethyl) benzoic acid with a melting point of 113-116 ° C. were obtained.

Diese Säure erhitzte man mit 0.37 ml Thionylchlorid auf 80°C. Nach 15 min entfernte man das Thionylchlorid i. Vak. und er­hielt 0.3 g (90 %) 4-(1-Cyanoethyl)benzoesäurechlorid als Öl, das man sofort ohne weitere Reinigung umsetzte.This acid was heated to 80 ° C. with 0.37 ml of thionyl chloride. After 15 min, the thionyl chloride was removed i. Vac. and obtained 0.3 g (90%) of 4- (1-cyanoethyl) benzoic acid chloride as an oil, which was immediately reacted without further purification.

Beispiel 22Example 22 N-(4-Methoxyphenyl)-4-(1-cyano-1-methylethyl)benzamidN- (4-methoxyphenyl) -4- (1-cyano-1-methylethyl) benzamide

Analog dem Beispiel 1 erhielt man durch Umsetzung von 1 g 4-­Methoxyanilin mit 1.86 g 4-(1-Cyano-1-methylethyl)benzoesäure­chlorid 1.64 g (69 %) der Titelverbindung als cremefarbenes Pulver mit dem Fp. 164-168°C nach Umkristallisation aus Methanol.Analogously to Example 1, 1.64 g (69%) of the title compound was obtained as a cream-colored powder with a melting point of 164-168 ° C. by reacting 1 g of 4-methoxyaniline with 1.86 g of 4- (1-cyano-1-methylethyl) benzoic acid chloride Recrystallization from methanol.

4-(1-Cyano-1-methylethyl)benzoesäurechlorid stellte man wie folgt her:
0.9 g 4-(Cyanomethyl)benzoesäuremethylester (J.F. Codington et al., J.Org.Chem. 17 (1952) 1035) und 0.15 g Tetrabutylammonium­bromid in 5 ml 50 % Natronlauge versetzte man unter Eiskühlung mit 1 ml Iodmethan. Man rührte 16 h bei Raumtemperatur und ar­beitet, wie in Beispiel 21 beschriebenen, auf. Man erhielt 1 g (96 %) 4-(1-Cyano-1-methylethyl)benzoesäuremethylester mit dem Fp. 45-50°C.4- (1-Cyano-1-methylethyl) benzoic acid chloride was prepared as follows:
0.9 g of methyl 4- (cyanomethyl) benzoate (JF Codington et al., J.Org.Chem. 17 (1952) 1035) and 0.15 g of tetrabutylammonium bromide in 5 ml of 50% sodium hydroxide solution were treated with 1 ml of iodomethane while cooling with ice. The mixture was stirred at room temperature for 16 h and worked up as described in Example 21. 1 g (96%) of methyl 4- (1-cyano-1-methylethyl) benzoate was obtained, mp 45-50 ° C.

0.5 g dieses Esters verseifte man wie in Beispiel 21 be­schrieben und erhielt 0.35 g (76 %) 4-(1-Cyano-1-methyl­ethyl)benzoesäure mit dem Fp. 172-178°C.0.5 g of this ester was saponified as described in Example 21 and 0.35 g (76%) of 4- (1-cyano-1-methylethyl) benzoic acid with the mp. 172-178 ° C. was obtained.

Die Säure versetzte man mit Thionylchlorid wie in Beispiel 21 beschrieben und erhielt 4-(1-Cyano-1-methylethyl)benzoesäure­chlorid als Öl, welches man ohne weitere Reinigung einsetzte.Thionyl chloride was added to the acid as described in Example 21 and 4- (1-cyano-1-methylethyl) benzoic acid chloride was obtained as an oil, which was used without further purification.

Beispiel 23Example 23 N-(4-Methoxyphenyl)-4-(1-aminocarbonyl-1-methylethyl)benzamidN- (4-methoxyphenyl) -4- (1-aminocarbonyl-1-methylethyl) benzamide

1 g N-(4-Methoxyphenyl)-4-(1-cyano-1-methylethyl)benzamid (Bei­spiel 22) in 6 ml Dichlormethan versetzte man unter Eiskühlung und kräftigem Rühren mit 1.59 ml H₂O₂ (30 %), 0.23 g Tetra­butylammoniumhydrogensulfat und 1.27 ml 20 % Natronlauge.1 g of N- (4-methoxyphenyl) -4- (1-cyano-1-methylethyl) benzamide (Example 22) in 6 ml of dichloromethane was treated with ice cooling and vigorous stirring with 1.59 ml of H₂O₂ (30%), 0.23 g of tetrabutylammonium hydrogen sulfate and 1.27 ml 20% sodium hydroxide solution.

Man rührte 8 h bei Raumtemperatur, trennte die organische Phase ab, entfernte das Lösungsmittel i.Vak. und reinigte den kristal­linen Rückstand säulenchromatographisch. (Kieselgel, n-Heptan/­Methylethylketon 1:1). Entsprechende Fraktionen wurden i.Vak. eingeengt. Man erhielt 0.16 g (15 %) der Titelverbindung mit dem Fp. 176-180°C.The mixture was stirred at room temperature for 8 h, the organic phase was separated off and the solvent was removed in vacuo. and purified the crystalline residue by column chromatography. (Silica gel, n-heptane / methyl ethyl ketone 1: 1). Corresponding fractions were i.Vak. constricted. 0.16 g (15%) of the title compound with mp 176-180 ° C. was obtained.

Beispiel 24Example 24 N-(4-(1,1-Dimethylethyl)phenyl)-4-methoxy-zimtsäureamidN- (4- (1,1-Dimethylethyl) phenyl) -4-methoxy-cinnamic acid amide

Unter den Reaktionsbedingungen von Beispiel 1 setzte man 4-­(1,1-Dimethylethyl)anilin (2.5 g) mit 4-Methoxyzimtsäurechlorid (2.5 g) um und erhielt 1.0 g der Titelverbindung mit dem Fp. 158-160°C.Under the reaction conditions of Example 1, 4- (1,1-dimethylethyl) aniline (2.5 g) was reacted with 4-methoxycinnamoyl chloride (2.5 g) and 1.0 g of the title compound with the mp. 158-160 ° C. was obtained.

Beispiel 25Example 25 4-(1,1-Dimethylethyl)-N-(4-methoxy-2-nitrophenyl)benzamid4- (1,1-dimethylethyl) -N- (4-methoxy-2-nitrophenyl) benzamide

Zu 16.8 g (0.1 mol) 4-Methoxy-2-nitroanilin in 150 ml wasser­freiem Pyridin tropfte man unter Kühlung mit Eiswasser 19.7 g (0.1 mol) 4-tert.Butylbenzoesäurechlorid. Man rührte noch 1 h bei Raumtemperatur, goß auf 1 L kaltes Wasser und saugte den Niederschlag ab. Man erhielt 32.3 g (98 %) der Titelverbindung mit dem Fp. 103-107°C in Form gelber Kristalle.19.8 g (0.1 mol) of 4-tert-butylbenzoic acid chloride were added dropwise to 16.8 g (0.1 mol) of 4-methoxy-2-nitroaniline in 150 ml of anhydrous pyridine while cooling with ice water. The mixture was stirred for a further 1 h at room temperature, poured into 1 L of cold water and the precipitate was filtered off with suction. This gave 32.3 g (98%) of the title compound with the mp. 103-107 ° C in the form of yellow crystals.

Beispiel 26Example 26 4-(2-Amino-1,1-dimethyl-ethyl)-N-(4-methoxyphenyl)benzamid4- (2-amino-1,1-dimethyl-ethyl) -N- (4-methoxyphenyl) benzamide

2 g 4-(1-Cyano-1-methyl-ethyl)-N-(4-methoxyphenyl)benzamid (Beispiel 22) in 100 ml 10 % ethanolischem Ammoniak hydrierte man in Gegenwart von 1 g 5 % Rhodium auf Aluminiumoxid 24 h bei 5 bar. Man saugte ab, engte das Filtrat zur Trockene ein und kristallisierte den Rückstand aus Ethanol um. Man erhielt 0.68 g (34 %) der Titelverbindung als farblose Kristalle mit dem Fp. 139-140°C.2 g of 4- (1-cyano-1-methyl-ethyl) -N- (4-methoxyphenyl) benzamide (Example 22) in 100 ml of 10% ethanolic ammonia were hydrogenated in the presence of 1 g of 5% rhodium on aluminum oxide for 24 hours 5 bar. It was suctioned off, the filtrate was evaporated to dryness and the residue was recrystallized from ethanol. 0.68 g (34%) of the title compound were obtained as colorless crystals with a melting point of 139-140 ° C.

Beispiel 27Example 27 N-[4-(1-Cyano-1-methylethyl)phenyl]-4-methoxy-benzamidN- [4- (1-Cyano-1-methylethyl) phenyl] -4-methoxy-benzamide

Analog dem Beispiel 25 setzte man 4-(1-Cyano-1-methylethyl)­anilin mit 4-Methoxybenzoesäurechlorid um und erhielt in 85 % Ausbeute die Titelverbindung mit dem Fp. 169-171°C als beige Kristalle. Eine Probe davon kristallisierte man aus Ethanol um und erhielt einen Fp. von 172-174°C.Analogously to Example 25, 4- (1-cyano-1-methylethyl) aniline was reacted with 4-methoxybenzoic acid chloride and the title compound with mp 169-171 ° C. was obtained in 85% yield as beige crystals. A sample of this was recrystallized from ethanol and an mp of 172-174 ° C was obtained.

Beispiel 28Example 28 N-[4-(1-Aminocarbonyl-1-methylethyl)phenyl]-4-methoxy-benzamidN- [4- (1-aminocarbonyl-1-methylethyl) phenyl] -4-methoxy-benzamide

5 g N-[4-(1-Cyano-1-methylethyl)phenyl]-4-methoxy-benzamid (Beispiel 27) rührte man 20 h bei Raumtemperatur in 100 ml konz. Schwefelsäure, goß auf Eis, saugte den Niederschlag ab, löste ihn in heißem Eisessig, gab Wasser bis zur beginnenden Trübung zu und ließ abkühlen. Man erhielt 2.2 g (42 %) der Titelverbindung als farblose Kristalle mit dem Fp. 234-235°C.5 g of N- [4- (1-cyano-1-methylethyl) phenyl] -4-methoxy-benzamide (Example 27) were stirred for 20 h at room temperature in 100 ml of conc. Sulfuric acid, poured onto ice, suctioned off the precipitate, dissolved it in hot glacial acetic acid, added water until the turbidity began and allowed to cool. 2.2 g (42%) of the title compound were obtained as colorless crystals with a melting point of 234-235 ° C.

Beispiel 29Example 29 N-[4-(2-Amino-1,1-dimethylethyl)phenyl]-4-methoxy-benzamidN- [4- (2-Amino-1,1-dimethylethyl) phenyl] -4-methoxy-benzamide

5 g N-[4-(1-Cyano-1-methylethyl)phenyl]-4-methoxy-benzamid (Beispiel 27) hydrierte man bei 90°C und 120 bar Wasserstoff­druck in 40 ml Ethanol in Gegenwart von 40 ml flüssigem Ammoniak und 2 g Raney-Nickel. Man filtrierte und engte das Filtrat im Vak. zur Trockene ein. nach säulenchromatogra­phischer Reinigung (400 ml Kieselgel 60, Dichlormethan/­methanol. Ammoniak = 30:1) erhielt man 2.6 g farblose Kristalle, die man in 100 ml 1 N Salzsäure erhitzte. Nach dem Abkühlen erhielt man 2.3 g (40 %) der Titelverbindung als Hydrochlorid mit dem Fp. 273-276°C als farblose Blättchen.5 g of N- [4- (1-cyano-1-methylethyl) phenyl] -4-methoxy-benzamide (Example 27) were hydrogenated at 90 ° C. and 120 bar hydrogen pressure in 40 ml of ethanol in the presence of 40 ml of liquid ammonia and 2 g of Raney nickel. The filtrate was filtered and concentrated in vacuo. to dry out. after purification by column chromatography (400 ml of silica gel 60, dichloromethane / methanol. ammonia = 30: 1), 2.6 g of colorless crystals were obtained, which were heated in 100 ml of 1N hydrochloric acid. After cooling, 2.3 g (40%) of the title compound were obtained as the hydrochloride with the melting point 273-276 ° C. as a colorless leaflet.

Beispiel 30Example 30 N-[4-(1,1-Dimethylethyl)phenyl]-4-methoxy-benzamidN- [4- (1,1-Dimethylethyl) phenyl] -4-methoxy-benzamide

Analog dem Beispiel 1 erhielt man aus 4-(1,1-Dimethylethyl)­anilin und 4-Methoxybenzoesäurechlorid die Titelverbindung in 65 % Ausbeute mit dem Fp. 167-168°C.Analogously to Example 1, the title compound was obtained from 4- (1,1-dimethylethyl) aniline and 4-methoxybenzoic acid chloride in 65% yield with a melting point of 167-168 ° C.

Beispiel 31Example 31 4-(1,1-Dimethylethyl)-N-[4-(ethoxycarbonylmethyloxy)phenyl]­benzamid4- (1,1-dimethylethyl) -N- [4- (ethoxycarbonylmethyloxy) phenyl] benzamide

Zu einer Lösung von 0.66 g Natrium in 25 ml Ethanol gab man 7 g 4-(1,1-Dimethylethyl)-N-(4-hydroxy-phenyl)benzamid (Beispiel 2) und 3.2 ml Bromessigsäureethylester. Man erhitzte 10 h unter Rückfluß zum Sieden, entfernte das Lösungsmittel i. Vak. und kristallisierte aus Toluol um. Man erhielt 5.5 g (60 %) der Titelverbindung mit dem Fp. 119-122°C.7 g of 4- (1,1-dimethylethyl) -N- (4-hydroxyphenyl) benzamide (Example 2) and 3.2 ml of ethyl bromoacetate were added to a solution of 0.66 g of sodium in 25 ml of ethanol. The mixture was heated to reflux for 10 h, the solvent was removed i. Vac. and recrystallized from toluene. 5.5 g (60%) of the title compound with mp 119-122 ° C. were obtained.

Beispiel 32Example 32 4-(1,1-Dimethylethyl)-N-[4-(hydroxycarbonylmethyloxy)phenyl]­benzamid4- (1,1-dimethylethyl) -N- [4- (hydroxycarbonylmethyloxy) phenyl] benzamide

2.0 g 4-(1,1-Dimethylethyl)-N-[4-(ethoxycarbonyl-methyloxy)­phenyl]benzamid (Beispiel 31) erhitzte man in 20 ml 2 N Natron­lauge, säuerte mit konz. Salzsäure an, saugte ab und wusch mit Wasser nach. Nach Umkristallisieren aus Essigester erhielt man 1.2 g (65 %) der Titelverbindung mit dem Fp. 179-181°C.2.0 g of 4- (1,1-dimethylethyl) -N- [4- (ethoxycarbonyl-methyloxy) phenyl] benzamide (Example 31) was heated in 20 ml of 2N sodium hydroxide solution, acidified with conc. Hydrochloric acid, sucked off and washed with water. After recrystallization from ethyl acetate, 1.2 g (65%) of the title compound with the mp. 179-181 ° C.

Beispiel 33Example 33 4-(1,1-Dimethylethyl)-N-[4-(3-(ethoxycarbonyl)propyloxy)­phenyl]benzamid4- (1,1-dimethylethyl) -N- [4- (3- (ethoxycarbonyl) propyloxy) phenyl] benzamide

analog dem Beispiel 31 erhielt man durch Umsetzung von 4-Brom­buttersäureethylester mit 4-(1,1-Dimethylethyl)-N-(4-hydroxy­phenyl)benzamid (Beispiel 2) die Titelverbindung in 56 % Aus­beute mit dem Fp. 100-101°C nach Umkristallisation aus Isopro­panol.Analogously to Example 31, reaction of ethyl 4-bromobutyrate with 4- (1,1-dimethylethyl) -N- (4-hydroxyphenyl) benzamide (Example 2) gave the title compound in 56% yield with the mp. 100-101 ° C. after recrystallization from isopropanol.

Beispiel 34Example 34 4-(1,1-Dimethylethyl)-N-[4-(3-(hydroxycarbonyl)propyloxy)­phenyl]benzamid4- (1,1-dimethylethyl) -N- [4- (3- (hydroxycarbonyl) propyloxy) phenyl] benzamide

Analog dem Beispiel 32 verseifte man die Verbindung des Bei­spiels 33 und erhielt die Titelverbindung mit dem Fp. 162-168°C in 67 % Ausbeute nach Umkristallisation aus Essigester.Analogously to Example 32, the compound from Example 33 was saponified and the title compound with the mp. 162-168 ° C. was obtained in 67% yield after recrystallization from ethyl acetate.

Beispiel 35Example 35 4-(1,1-Dimethylethyl)-N-[4-(((N′-cyclohexyl-N′-methyl-amino)­carbonyl)propyloxy)phenyl]benzamid4- (1,1-Dimethylethyl) -N- [4 - (((N'-cyclohexyl-N'-methylamino) carbonyl) propyloxy) phenyl] benzamide

1.7 g der in Beispiel 34 erhaltenen Säure und 10 ml Thionyl­chlorid erhitzte man 1.5 h unter Rückfluß zum Sieden. Man entfernte das Thionylchlorid i.Vak. versetzte den Rückstand mit 15 ml Dichlormethan und 1 ml N-Cyclohexyl-N-methylamin und rührte 2 h bei Raumtemperatur. Man schüttelte mit Wasser, dampfte die organische Phase zur Trockene ein und reinigte den Rückstand säulenchromatographisch (Dichlormethan/Methanol 98:2). Nach Eindampfen der gewünschten Fraktionen und Um­kristallisation des Rückstandes aus Essigester erhielt man 0.5 g (26 %) der Titelverbindung mit dem Fp. 110-113°C.1.7 g of the acid obtained in Example 34 and 10 ml of thionyl chloride were heated to boiling under reflux for 1.5 h. The thionyl chloride was removed in vacuo. 15 ml of dichloromethane and 1 ml of N-cyclohexyl-N-methylamine were added to the residue and the mixture was stirred at room temperature for 2 h. It was shaken with water, the organic phase was evaporated to dryness and the residue was purified by column chromatography (dichloromethane / methanol 98: 2). After evaporation of the desired fractions and recrystallization of the residue from ethyl acetate, 0.5 g (26%) of the title compound with mp 110-113 ° C. was obtained.

Beispiel 36Example 36 4-(1,1-Dimethylethyl)-N-[4-(hydroxyethyloxy)phenyl]benzamid4- (1,1-dimethylethyl) -N- [4- (hydroxyethyloxy) phenyl] benzamide

2.2 g der Verbindung aus Beispiel 31 reduzierte man mit 0.65 g Lithiumaluminiumhydrid in 50 ml siedendem Diethylether. Man versetzte mit Wasser, gab soviel 10 % Schwefelsäure zu, daß sich der Niederschlag gerade löste, extrahierte mit Ether, dampfte zur Trockene ein und reinigte das zurückbleibende Öl säulenchromatographisch (Kieselgel, Dichlormethan, Methanol 99:1). Entsprechende Fraktionen engte man im Vak. zur Trockene ein, kristallisierte den Rückstand zuerst in Essigester/Ligroin (1:1) und dann mit Toluol um und erhielt so 0.6 g (31 %) der Titelverbindung mit dem Fp. 136-142°C.2.2 g of the compound from Example 31 were reduced with 0.65 g of lithium aluminum hydride in 50 ml of boiling diethyl ether. Water was added, so much 10% sulfuric acid was added that the precipitate was just dissolving, extracted with ether, evaporated to dryness and the remaining oil purified column chromatography (silica gel, dichloromethane, methanol 99: 1). Corresponding fractions were narrowed in the vac. to dryness, the residue was recrystallized first in ethyl acetate / ligroin (1: 1) and then with toluene, giving 0.6 g (31%) of the title compound, mp 136-142 ° C.

Beispiel 37Example 37 4-(1,1-Dimethylethyl)-N-[(4-methoxyphenyl)methyl]benzamid4- (1,1-dimethylethyl) -N - [(4-methoxyphenyl) methyl] benzamide

Analog dem Beispiel 1 erhielt man aus 4-(1,1-Dimethylethyl)­benzoesäurechlorid und 4-(Methoxyphenyl)methylamin die Titel­verbindung in 71 % Ausbeute mit dem Fp. 145-148°C nach Umkristallisation aus Isohexan.Analogously to Example 1, the title compound was obtained from 4- (1,1-dimethylethyl) benzoic acid chloride and 4- (methoxyphenyl) methylamine in 71% yield with a melting point of 145-148 ° C. after recrystallization from isohexane.

Beispiel 38Example 38 4-(1,1-Dimethylethyl)-N-[2-nitro-4-(3-pyridinyloxy)phenyl]­benzamid4- (1,1-dimethylethyl) -N- [2-nitro-4- (3-pyridinyloxy) phenyl] benzamide

Zu 2.35 g 4-(1,1-Dimethylethyl)-N-[4-(3-pyridinyloxy)phenyl)­benzamid in 60 ml Essigsäureanhydrid tropfte man innerhalb 2 h 2.7 ml 100 % HNO₃ (d = 1.52), goß auf Eis, extrahierte mit Dichlormethan, entfernte das Lösungsmittel i. Vak. und kristal­lisierte aus Toluol/Ligroin um. Man erhielt 0.82 g (31 %) der Titelverbindung mit dem Fp. 103°C.2.7 ml of 100% HNO 3 (d = 1.52) were added dropwise to 2.35 g of 4- (1,1-dimethylethyl) -N- [4- (3-pyridinyloxy) phenyl) benzamide in 60 ml of acetic anhydride, poured onto ice, extracted with dichloromethane, removed the solvent i. Vac. and recrystallized from toluene / ligroin. 0.82 g (31%) of the title compound with mp 103 ° C. was obtained.

Beispiel 39Example 39 4-(1-Cyanocyclopentyl)-N-(4-methoxyphenyl)-benzamid4- (1-cyanocyclopentyl) -N- (4-methoxyphenyl) benzamide

  • a) Zu 22.3 g (127 mmol) 4-(Cyanomethyl)-benzoesäure­methylester (J.F. Codington, E. Mosettig; J.Org.Chem. 17 (1952) 1032) und 1.1 g Benzyltributylammoniumbromid in 87 ml konz. Natronlauge tropfte man rasch 16.5 ml (140 mmol) 1,4-Dibrombutan. Die Temperatur steig auf 70°C. Man rührte 2 h, wobei die Lösung auf Raumtemperatur abkühlte. Man gab 500 ml Eiswasser zu und extrahierte mit Dichlormethan. Die organische Phase schüttelte man mit Wasser aus, trocknete sie über Natriumsulfat, filtrierte und engte i. Vak. zur Trockene ein. Den Rückstand filtrierte man mit Dichlormethan über eine Säule (L = 50 cm, 0̸ = 5 cm, Kieselgel "60"). Nach Entfernen des Lösungsmittels i. Vak. erhielt man 21 g (72 %) 4-(1-­Cyanocyclopentyl)-benzoesäuremethylester mit Fp. 32-33°C.a) To 22.3 g (127 mmol) of 4- (cyanomethyl) benzoic acid methyl ester (JF Codington, E. Mosettig; J.Org.Chem. 17 (1952) 1032) and 1.1 g of benzyltributylammonium bromide in 87 ml conc. 16.5 ml (140 mmol) 1,4-dibromobutane. The temperature rises to 70 ° C. The mixture was stirred for 2 h, during which the solution cooled to room temperature. 500 ml of ice water were added and the mixture was extracted with dichloromethane. The organic phase was shaken out with water, dried over sodium sulfate, filtered and concentrated i. Vac. to dry out. The residue was filtered with dichloromethane on a column (L = 50 cm, 0̸ = 5 cm, silica gel "60"). After removing the solvent i. Vac. 21 g (72%) of methyl 4- (1-cyanocyclopentyl) benzoate were obtained, mp 32-33 ° C.
  • b) 19.4 g (85 mmol) 4-(1-Cyanocyclopenyl)­benzoesäuremethylester bewahrte man 20 h bei Raumtemperatur in 180 ml Methanol und 60 ml 2 N Natronlauge auf. Man entfernte das Lösungsmittel i. Vak., säuerte mit 6 N Salzsäure an, filtrierte und wusch das Filtrat mit Wasser. Man erhielt 18 g 4-(1-­Cyanocyclopentyl)-benzoesäure (98 %) mit den Fp. 170-­174°C.b) 19.4 g (85 mmol) of methyl 4- (1-cyanocyclopenyl) benzoate were stored for 20 h at room temperature in 180 ml of methanol and 60 ml of 2N sodium hydroxide solution. The solvent was removed i. Vac., Acidified with 6N hydrochloric acid, filtered and washed the filtrate with water. 18 g of 4- (1-cyanocyclopentyl) benzoic acid (98%) were obtained with the mp. 170-174 ° C.
  • c) 5.8 g (27 mmol) 4-(1-Cyanocyclopentyl)benzoesäure setzte man mit Thionylchlorid und anschließend mit 4-­Methoxyanilin um wie in Beispiel 1 beschrieben, und erhielt 5.1 g (59 %) der Titelverbindung mit dem Fp. 163-­168°C.c) 5.8 g (27 mmol) of 4- (1-cyanocyclopentyl) benzoic acid were reacted with thionyl chloride and then with 4-methoxyaniline as described in Example 1, and 5.1 g (59%) of the title compound with mp 163-168 were obtained ° C.
Beispiel 40Example 40 4-(1,1-Dimethylethyl)-N-(4-(2-hydroxyethyloxy)phenyl)-benzamid4- (1,1-dimethylethyl) -N- (4- (2-hydroxyethyloxy) phenyl) benzamide

2.2 g (6.2 mmol) der in Beispiel 31 hergestellten Titelverbindung in 50 ml trockenem Ether erhitzte man mit 1 g LiAlH₄, gab anschließend Wasser und wenig 10 % H₂SO₄ zu, extrahierte mit Ether, trocknete über Na₂SO₄, filtrierte, entfernte das Lösungsmittel i. Vak. und kristallisierte den Rückstand aus Toluol um. Fp. 136-142°C. Ausbeute 25 %.2.2 g (6.2 mmol) of the title compound prepared in Example 31 in 50 ml of dry ether was heated with 1 g of LiAlH₄, then water and a little 10% H₂SO₄ were added, extracted with ether, dried over Na₂SO₄, filtered, the solvent was removed i. Vac. and recrystallized the residue from toluene. Mp 136-142 ° C. Yield 25%.

Claims (11)

1. Verfahren zur Herstellung von Arzneimitteln, dadurch ge­kennzeichnet, daß man eine Verbindung der Formel I
Figure imgb0013
 in der
R₁, R₂, R₃, gleich oder verschieden sein können und jeweils ein Wasserstoffatom, eine C₁-C₆-Alkyl-, C₂-C₆-Alkenyl-, C₂-C₆-Alkinyl-, C₃-C₇-Cycloalkyl-, C₃-C₇-Cycloalkenyl-, Phenyl-, Halogen-, Nitro-, Amino-, Formyl-, Hydroxy-, Mercapto-, Cyanogruppe, eine durch eine C₁-C₆-Alkyl-, C₂-C₆-Alkenyl-, C₂-C₆-Alkinyl-, C₃-C₇-Cycloalkyl-, C₃-­C₇-Cycloalkenyl-, Phenyl-, Benzyl-, Pyridinyl-, C₁-C₆-­Alkylsulfonyl-, Trifluormethylsulfonyl-, C₁-C₆-­Alkylcarbonyl-, Cyanalkyl-, Hydroxy-C₁-C₆-alkyl-, Di-C₁-­C₆-alkylamino-C₁-C₆-alkyl-, Aminocarbonyl-C₁-C₆-alkyl-, Di-C₁-C₆-alkylaminocarbonyl-C₁-C₆-alkyl-, N-Cycloalkyl-­N-C₁-C₆-alkylaminocarbonyl-C₁-C₆-alkyl-, Carboxy-C₁-C₆-­alkyl-, C₁-C₆-Alkoxycarbonyl-C₁-C₆-alkyl- oder C₁-C₆-­alkoxy-C₁-C₆-alkylgruppe substituierte Hydroxygruppe, eine durch eine oder zwei C₁-C₆-Alkylsulfonyl-, Trifluormethylsulfonyl-, C₁-C₆-Alkylcarbonyl-, Formyl-, Aminocarbonyl-, C₁-C₆-Alkylaminocarbonyl- oder C₁-C₆-­Alkylgruppen substituierte Aminogruppe, eine durch eine Hydroxy-, C₁-C₆-Alkyl-, C₁-C₆-Alkoxy-, Amino-, C₁-C₆-­Alkylamino- oder Di-C₁-C₆-alkylaminogruppe substituierte Carbonylgruppe, eine durch eine Amino-, C₁-C₆-­Alkylamino-, Piperidino-, Morpholino- oder Thiomorpholinogruppe substituierte Sulfonylgruppe, eine C₁-C₆-Alkylthio-, C₁-C₆-Alkylsulfinyl- oder C₁-C₆-­Alkylsulfonylgruppe bedeuten können, oder in der zwei zueinander ortho-ständige Substituenten R₂ und R₃ zusammen mit den C-Atomen, an die sie gebunden sind, einen fünf- oder sechsgliedrigen Ring bilden,
X      eine Bindung, eine C₁-C₆-Alkylengruppe, oder für den Fall, daß A die Carbonylgruppe -CO- bedeutet, auch die C₂-C₆-Alkenylengruppe bedeuten kann, und
A und B verschieden sind und die Carbonylgruppe -CO- oder die Iminogruppe -NH- bedeuten, und
R₄      eine Methyl-, Cyano-, Aminocarbonyl- oder Aminomethylgruppe bedeutet,
R₅      ein Wasserstoffatom, oder eine C₁-C₆-Alkylgruppe bedeutet,
R₆      eine C₁-C₆-Alkyl- oder C₃-C₇-Cycloalkylgruppe bedeutet,
oder
R₅ und R₆ zusammen mit dem C-Atom, an das sie gebunden sind, einen C₃-C₇-Cycloalkylring bedeuten,
deren optisch aktiven Formen, deren Tautomere und deren physiologisch verträglichen Salze anorganischer und organischer Säuren, mit Ausnahme der Verbindung 4-(1,1-­Dimethylethyl)-N-[2-(1H-imidazol-1-yl)phenyl]benzamid, sowie der Maßgabe, daß für den Fall, daß R₄, R₅, R₆ eine Methylgruppe, B eine Carbonylgruppe -CO-, A eine Iminogruppe -NH-, X einen Valenzstrich und einer der Substituenten R₁, R₂, R₃ in meta-Position des Phenylrings die Trifluormethylgruppe bedeutete, die beiden anderen Substituenten R₁, R₂, R₃ nicht ein Wasserstoff- oder Halogenatom, oder die Trifluormethylgruppe sein können,
zusammen mit physiologisch verträglichen Träger- oder Hilfsstoffen in eine geeignete Darreichungsform bringt.1. A process for the preparation of medicaments, characterized in that a compound of formula I.
Figure imgb0013
 in the
R₁, R₂, R₃, may be the same or different and each have a hydrogen atom, a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl -, Phenyl, halogen, nitro, amino, formyl, hydroxy, mercapto, cyano group, one by a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃ -C₇-cycloalkyl-, C₃-C₇-cycloalkenyl-, phenyl-, benzyl-, pyridinyl-, C₁-Culf-alkylsulfonyl-, trifluoromethylsulfonyl-, C₁-C₆-alkylcarbonyl-, cyanoalkyl, hydroxy-C₁-C₆-alkyl- , Di-C₁-C₆-alkylamino-C₁-C₆-alkyl-, aminocarbonyl-C₁-C₆-alkyl-, di-C₁-C₆-alkylaminocarbonyl-C₁-C₆-alkyl-, N-cycloalkyl-N-C₁-C₆- alkylaminocarbonyl-C₁-C₆-alkyl, carboxy-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl group, substituted by one or two C₁-C₆ alkylsulfonyl, trifluoromethylsulfonyl, C₁-C₁ alkylcarbonyl, formyl, Aminocarbonyl, C₁-C₆-alkylaminocarbonyl or C₁-C₆-alkyl groups, an amino group substituted by a hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino or di- C₁-C₆-alkylamino group substituted carbonyl group, a sulfonyl group substituted by an amino, C₁-C₆-alkylamino, piperidino, morpholino or thiomorpholino group, a C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl or C₁-C₆- Can mean alkylsulfonyl group, or in which two mutually ortho-standing substituents R₂ and R₃ together with the C atoms to which they are attached form a five- or six-membered ring,
X is a bond, a C₁-C₆-alkylene group, or in the event that A is the carbonyl group -CO-, can also mean the C₂-C Al-alkenylene group, and
A and B are different and represent the carbonyl group -CO- or the imino group -NH-, and
R₄ represents a methyl, cyano, aminocarbonyl or aminomethyl group,
R₅ represents a hydrogen atom or a C₁-C₆ alkyl group,
R₆ represents a C₁-C₆-alkyl or C₃-C₇-cycloalkyl group,
or
R₅ and R₆ together with the carbon atom to which they are attached mean a C₃-C₇ cycloalkyl ring,
their optically active forms, their tautomers and their physiologically tolerable salts of inorganic and organic acids, with the exception of the compound 4- (1,1-dimethylethyl) -N- [2- (1H-imidazol-1-yl) phenyl] benzamide, and the proviso that in the event that R₄, R₅, R₆ a methyl group, B a carbonyl group -CO-, A an imino group -NH-, X a valence line and one of the substituents R₁, R₂, R₃ in the meta position of the phenyl ring Trifluoromethyl group meant the two other substituents R₁, R₂, R₃ cannot be a hydrogen or halogen atom, or the trifluoromethyl group,
brings together with physiologically compatible carriers or excipients in a suitable dosage form. 2. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man eine Verbindung der Formel I verwendet, in der
R₁      ein Wasserstoffatom, die Nitro-, Amino-, Fluor-, Chlor-, Brom-, Dimethylamino-, Diethylamino-, Cyano-, Methyl-, Ethyl-, n-Propyl-, i-Propyl-, n-Butyl-, i-­Butyl-, tert.-Butyl-, Allyl-, Hydroxy-, Methoxy-, Ethoxy-, Propyloxy-, Allyloxy-, Mercapto-, Methylthio-, Methylsulfinyl-, Methylsulfonyl-, Methylsulfonyloxy-, Cyanmethyloxy-, Benzyloxy-, Pyridinyloxy-, Ethoxycarbonylmethyloxy-, Carboxy-, Ethyloxycarbonyl-, Hydroxymethyl-, Formyl-amino-, Acetylamino-, Methylsulfonylamino- und die Trifluormethylsulfonylaminogruppe bedeuten kann,
R₂      ein Wasserstoffatom, die Methyl-, Ethyl-, n-Propyl-, i-­Propyl-, tert.-Butyl-, Chlor-, Methoxy-, Hydroxy- oder Dimethylaminogruppe bedeutet,
R₃      ein Wasserstoffatom, die Hydroxy- oder Methoxygruppe bedeutet,
X      eine Bindung, die Ethylengruppe oder für den Fall, daß A die Carbonylgruppe bedeutet, auch die Vinylengruppe bedeutet,
A und B verschieden sind und die Imino- und die Carbonyl­gruppe bedeuten,
R₄      die Methyl-, Cyano-, Aminocarbonyl- oder Aminomethyl­gruppe bedeutet,
R₅      ein Wasserstoffatom, die Methyl- oder Ethylgruppe bedeutet,
R₆      die Methylgruppe, Ethylgruppe oder Cyclopentylgruppe bedeutet, oder
R₅ und R₆ zusammen mit dem C-Atom, an das sie gebunden sind, die Cyclopentylgruppe bedeuten.2. The method according to claim 1, characterized in that one uses a compound of formula I in which
R₁ is a hydrogen atom, the nitro, amino, fluorine, chlorine, bromine, dimethylamino, diethylamino, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, allyl, hydroxy, methoxy, ethoxy, propyloxy, allyloxy, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methylsulfonyloxy, cyanomethyloxy, benzyloxy, Pyridinyloxy, ethoxycarbonylmethyloxy, carboxy, ethyloxycarbonyl, hydroxymethyl, formylamino, acetylamino, methylsulfonylamino and the trifluoromethylsulfonylamino group,
R₂ is a hydrogen atom which means methyl, ethyl, n-propyl, i-propyl, tert-butyl, chlorine, methoxy, hydroxyl or dimethylamino group,
R₃ is a hydrogen atom, which means hydroxyl or methoxy group,
X represents a bond which represents the ethylene group or, if A represents the carbonyl group, also the vinylene group,
A and B are different and denote the imino and the carbonyl group,
R₄ represents the methyl, cyano, aminocarbonyl or aminomethyl group,
R₅ is a hydrogen atom which means methyl or ethyl group,
R₆ represents the methyl group, ethyl group or cyclopentyl group, or
R₅ and R₆ together with the carbon atom to which they are attached mean the cyclopentyl group. 3. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man eine Verbindung der Formel I verwendet, in der R₁ den Substituenten in ortho-Position des Phenylrings darstellt und ein Wasserstoff- oder Chloratom, eine C₁-C₄-Alkoxy- oder Nitrogruppe bedeutet.3. The method according to claim 1, characterized in that one uses a compound of formula I in which R₁ represents the substituent in the ortho position of the phenyl ring and is a hydrogen or chlorine atom, a C₁-C₄ alkoxy or nitro group. 4. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man eine Verbindung der Formel I verwendet, in der R₂ den Substituenten in meta-Position des Phenylrings darstellt und ein Wasserstoff- oder Chloratom, oder eine C₁-C₄-­Alkoxygruppe bedeutet.4. The method according to claim 1, characterized in that one uses a compound of formula I in which R₂ represents the substituent in the meta position of the phenyl ring and is a hydrogen or chlorine atom, or a C₁-C₄ alkoxy group. 5. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man eine Verbindung der Formel I verwendet, in der R₃ den Substituenten in para-Position des Phenylrings darstellt, und ein Wasserstoff- oder Halogenatom, eine C₁-C₄-Alkyl-, C₂-C₄-Alkenyl-, Nitro-, Amino-, Hydroxy-, Cyano-, C₁-C₄-­Alkoxy-, Benzyloxy-, 3-Pyridinyloxy-, C₁-C₄-­Alkylsulfonyloxy-, Hydroxy-C₁-C₄-alkyloxy-, Carboxy-C₁-C₄-­alkoxy-, C₁-C₄-Alkoxycarbonyl-C₁-C₄-alkoxy-, Di-C₁-C₄-­alkylamino-, oder N-C₅-C₆-Cycloalkyl-N-C₁-C₄-alkyl­aminocarbonyl-C₁-C₄-alkoxygruppe darstellt.5. The method according to claim 1, characterized in that one uses a compound of formula I in which R₃ represents the substituent in the para position of the phenyl ring, and a hydrogen or halogen atom, a C₁-C₄-alkyl, C₂-C₄ -Alkenyl, nitro, amino, hydroxy, cyano, C₁-C₄ alkoxy, benzyloxy, 3-pyridinyloxy, C₁-C₄ alkylsulfonyloxy, hydroxy-C₁-C₄ alkyloxy, carboxy-C₁ -C₄-alkoxy-, C₁-C₄-alkoxycarbonyl-C₁-C₄-alkoxy-, di-C₁-C₄-alkylamino-, or N-C₅-C₆-cycloalkyl-N-C₁-C₄-alkylaminocarbonyl-C₁-C₄-alkoxy group represents. 6. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man eine Verbindung der Formel I verwendet, in der R₄ die Methyl- oder Cyanogruppe bedeutet, oder R₅ eine C₁-C₄-­Alkylgruppe oder ein Wasserstoffatom darstellt, oder R₆ eine C₁-C₆-Alkylgruppe ist, oder R₅ und R₆ gemeinsam mit dem C-Atom, an das sie gebunden sind, einen Cyclopentyl- oder Cyclohexylring bilden.6. The method according to claim 1, characterized in that one uses a compound of formula I in which R₄ represents the methyl or cyano group, or R₅ represents a C₁-C₄ alkyl group or a hydrogen atom, or R₆ is a C₁-C₆ alkyl group is, or R₅ and R₆ together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl ring. 7. Verfahren gemäß einem der Ansprüche 1-6 zur Herstellung von Arzneimitteln zur Behandlung von Herz- und Kreislauf­erkrankungen, insbesondere von Arzneimitteln mit erythrozytenaggregationshemmender Wirkung.7. The method according to any one of claims 1-6 for the manufacture of medicaments for the treatment of cardiovascular diseases, in particular medicaments with an erythrocyte aggregation-inhibiting effect. 8. Verfahren zur Herstellung von Verbindungen der Formel I
Figure imgb0014
 in der
R₁, R₂, R₃, gleich oder verschieden sein können und jeweils ein Wasserstoffatom, eine C₁-C₆-Alkyl-, C₂-C₆-Alkenyl-, C₂-C₆-Alkinyl-, C₃-C₇-Cycloalkyl-, C₃-C₇-Cycloalkenyl-, Phenyl-, Halogen-, Nitro-, Amino-, Formyl-, Hydroxy-, Mercapto-, Cyanogruppe, eine durch eine C₁-C₆-Alkyl-, C₂-C₆-Alkenyl-, C₂-C₆-Alkinyl-, C₃-C₇-Cycloalkyl-, C₃-­C₇-Cycloalkenyl-, Phenyl-, Benzyl-, Pyridinyl-, C₁-C₆-­Alkylsulfonyl-, Trifluormethylsulfonyl-, C₁-C₆-­Alkylcarbonyl-, Cyanalkyl-, Hydroxy-C₁-C₆-alkyl-, Di-C₁-­C₆-alkylamino-C₁- C₆-alkyl-, Aminocarbonyl-C₁-C₆-alkyl-, Di-C₁-C₆-alkylaminocarbonyl-C₁-C₆-alkyl-, N-Cycloalkyl-­N-C₁-C₆-alkylaminocarbonyl-C₁-C₆-alkyl-, Carboxy-C₁-C₆-­alkyl-, C₁-C₆-Alkoxycarbonyl-C₁-C₆-alkyl- oder C₁-C₆-­alkoxy-C₁-C₆-alkylgruppe substituierte Hydroxygruppe, eine durch eine oder zwei C₁-C₆-Alkylsulfonyl-, Trifluormethylsulfonyl-, C₁-C₆-Alkylcarbonyl-, Formyl-, Aminocarbonyl-, C₁-C₆-Alkylaminocarbonyl- oder C₁-C₆-­Alkylgruppen substituierte Aminogruppe, eine durch eine Hydroxy-, C₁-C₆-Alkyl-, C₁-C₆-Alkoxy-, Amino-, C₁-C₆-­Alkylamino- oder Di-C₁-C₆-alkylaminogruppe substituierte Carbonylgruppe, eine durch eine Amino-, C₁-C₆-­Alkylamino-, Piperidino-, Morpholino- oder Thiomorpholinogruppe substituierte Sulfonylgruppe, eine C₁-C₆-Alkylthio-, C₁-C₆-Alkylsulfinyl- oder C₁-C₆-­Alkylsulfonylgruppe bedeuten können, oder in der zwei zueinander ortho-ständige Substituenten R₂ und R₃ zusammen mit den C-Atomen, an die sie gebunden sind, einen fünf- oder sechsgliedrigen Ring bilden,
X      eine Bindung, eine C₁-C₆-Alkylengruppe, oder für den Fall, daß A die Carbonylgruppe -CO- bedeutet, auch die C₂-C₆-Alkenylengruppe bedeuten kann, und
A und B verschieden sind und die Carbonylgruppe -CO- oder die Aminogruppe -NH- bedeuten, und
R₄      eine Methyl-, Cyano-, Aminocarbonyl- oder Aminomethylgruppe bedeutet,
R₅      ein Wasserstoffatom, oder eine C₁-C₆-Alkylgruppe bedeutet,
R₆      eine C₁-C₆-Alkyl- oder C₃-C₇-Cycloalkylgruppe bedeutet,
oder
R₅ und R₆ zusammen mit dem C-Atom, an das sie gebunden sind, einen C₃-C₇-Cycloalkylring bedeuten,
deren Tautomere, deren physiologisch vertraglichen Salze sowie deren optische Isomeren,
dadurch gekennzeichnet, daß man in an sich bekannter Weise entweder
a) eine Verbindung der Formel II
Figure imgb0015
 in der R₁, R₂ und X die angegebene Bedeutung haben, mit einer Verbindung der Formel III
Figure imgb0016
 in der R₄, R₅ und R₆ die angegebene Bedeutung haben, und Y Hydroxy, Halogen, C₁-C₄-Alkoxy, Phenyloxy, C₁-C₄-­Alkylcarbonyloxy oder Benzoyloxy darstellt,
umsetzt,
oder
b) eine Verbindung der Formel IV
Figure imgb0017
 in der R₁, R₂, R₃, X und Y die angegebene Bedeutung haben,
mit einer Verbindung der Formel V
Figure imgb0018
 in der R₄, R₅ und R₆ die angegebene Bedeutung haben,
umsetzt,
und anschließend gewünschtenfalls Verbindungen der Formel I in andere Verbindungen der Formel I umwandelt, die Verbindungen in unbedenkliche Salze überführt sowie die optischen Isomeren in üblicher Weise isoliert.8. Process for the preparation of compounds of formula I.
Figure imgb0014
 in the
R₁, R₂, R₃, may be the same or different and each have a hydrogen atom, a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkenyl -, Phenyl, halogen, nitro, amino, formyl, hydroxy, mercapto, cyano group, one by a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃ -C₇-cycloalkyl-, C₃-C₇-cycloalkenyl-, phenyl-, benzyl-, pyridinyl-, C₁-Culf-alkylsulfonyl-, trifluoromethylsulfonyl-, C₁-C₆-alkylcarbonyl-, cyanoalkyl, hydroxy-C₁-C₆-alkyl- , Di-C₁-C₆-alkylamino-C₁- C₆-alkyl-, aminocarbonyl-C₁-C₆-alkyl-, di-C₁-C₆-alkylaminocarbonyl-C₁-C₆-alkyl-, N-cycloalkyl-N-C₁-C₆- alkylaminocarbonyl-C₁-C₆-alkyl, carboxy-C₁-C₆-alkyl, C₁-C₆-alkoxycarbonyl-C₁-C₆-alkyl or C₁-C₆-alkoxy-C₁-C₆-alkyl group, substituted by one or two C₁-C₆ alkylsulfonyl, trifluoromethylsulfonyl, C₁-C₁ alkylcarbonyl, formyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl or C₁-C₆-alkyl groups substituted amino, one with a hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino or di-C₁-C₆ -alkylamino group substituted carbonyl group, a sulfonyl group substituted by an amino, C₁-C₆-alkylamino, piperidino, morpholino or thiomorpholino group, a C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl or C₁-C₆-alkylsulfonyl group , or in which two mutually ortho-standing substituents R₂ and R₃ together with the C atoms to which they are attached form a five- or six-membered ring,
X is a bond, a C₁-C₆-alkylene group, or in the event that A is the carbonyl group -CO-, can also mean the C₂-C Al-alkenylene group, and
A and B are different and are the carbonyl group -CO- or the amino group -NH-, and
R₄ represents a methyl, cyano, aminocarbonyl or aminomethyl group,
R₅ represents a hydrogen atom or a C₁-C₆ alkyl group,
R₆ represents a C₁-C₆-alkyl or C₃-C₇-cycloalkyl group,
or
R₅ and R₆ together with the carbon atom to which they are attached mean a C₃-C₇ cycloalkyl ring,
their tautomers, their physiologically acceptable salts and their optical isomers,
characterized in that either
a) a compound of formula II
Figure imgb0015
 in which R₁, R₂ and X have the meaning given, with a compound of formula III
Figure imgb0016
 in which R₄, R₅ and R₆ have the meaning given and Y is hydroxyl, halogen, C₁-C₄alkoxy, phenyloxy, C₁-C₄alkylcarbonyloxy or benzoyloxy,
implements
or
b) a compound of formula IV
Figure imgb0017
 in which R₁, R₂, R₃, X and Y have the meaning given,
with a compound of formula V
Figure imgb0018
 in which R₄, R₅ and R₆ have the meaning given,
implements
and then, if desired, converting compounds of the formula I into other compounds of the formula I, converting the compounds into harmless salts and isolating the optical isomers in the customary manner. 9. Verfahren zur Herstellung von Verbindungen gemäß Anspruch 8, dadurch gekennzeichnet, daß
R₁      ein Wasserstoffatom, die Nitro-, Amino-, Fluor-, Chlor-, Brom-, Dimethylamino-, Diethylamino-, Cyano-, Methyl-, Ethyl-, n-Propyl-, i-Propyl-, n-Butyl-, i-­Butyl-, tert.-Butyl-, Allyl-, Hydroxy-, Methoxy-, Ethoxy-, Propyloxy-, Allyloxy-, Mercapto-, Methylthio-, Methylsulfinyl-, Methylsulfonyl-, Methylsulfonyloxy-, Cyanmethyloxy-, Benzyloxy-, Pyridinyloxy-, Ethoxycarbonylmethyloxy-, Carboxy-, Ethyloxycarbonyl-, Hydroxymethyl-, Formyl-amino-, Acetylamino-, Methylsulfonylamino- und die Trifluormethylsulfonylaminogruppe bedeuten kann,
R₂      ein Wasserstoffatom, die Methyl-, Ethyl-, n-Propyl-, i-­Propyl-, tert.-Butyl-, Chlor-, Methoxy-, Hydroxy- oder Dimethylaminogruppe bedeutet,
R₃      ein Wasserstoffatom, die Hydroxy- oder Methoxygruppe bedeutet,
X      eine Bindung, die Ethylengruppe oder für den Fall, daß A die Carbonylgruppe bedeutet, auch die Vinylengruppe bedeutet,
A und B verschieden sind und die Imino- und die Carbonylgruppe bedeuten,
R₄      die Methyl-, Cyano-, Aminocarbonyl- oder Aminomethyl­gruppe bedeutet,
R₅      ein Wasserstoffatom, die Methyl- oder Ethylgruppe bedeutet,
R₆      die Methylgruppe, Ethylgruppe oder Cyclopentylgruppe bedeutet, oder
R₅ und R₆ zusammen mit dem C-Atom, an das sie gebunden sind, die Cyclopentylgruppe bedeuten.9. A process for the preparation of compounds according to claim 8, characterized in that
R₁ is a hydrogen atom, the nitro, amino, fluorine, chlorine, bromine, dimethylamino, diethylamino, cyano, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, allyl, hydroxy, methoxy, ethoxy, propyloxy, allyloxy, mercapto, methylthio, methylsulfinyl, methylsulfonyl, methylsulfonyloxy, cyanomethyloxy, benzyloxy, Pyridinyloxy, ethoxycarbonylmethyloxy, carboxy, ethyloxycarbonyl, hydroxymethyl, formylamino, acetylamino, methylsulfonylamino and the trifluoromethylsulfonylamino group,
R₂ is a hydrogen atom which means methyl, ethyl, n-propyl, i-propyl, tert-butyl, chlorine, methoxy, hydroxyl or dimethylamino group,
R₃ is a hydrogen atom, which means hydroxyl or methoxy group,
X represents a bond which represents the ethylene group or, if A represents the carbonyl group, also the vinylene group,
A and B are different and denote the imino and the carbonyl group,
R₄ represents the methyl, cyano, aminocarbonyl or aminomethyl group,
R₅ is a hydrogen atom which means methyl or ethyl group,
R₆ represents the methyl group, ethyl group or cyclopentyl group, or
R₅ and R₆ together with the carbon atom to which they are attached mean the cyclopentyl group. 10. Verfahren zur Herstellung von Arzneimitteln, dadurch ge­kennzeichnet, daß man eine Verbindung der Formel I mit den in den Ansprüchen 8 und 9 angegebenen Definitionen zusammen mit physiologisch verträglichen Träger- oder Hilfsstoffen in eine geeignete Darreichungsform bringt.10. A process for the preparation of medicaments, characterized in that a compound of the formula I with the definitions given in claims 8 and 9 is brought into a suitable dosage form together with physiologically tolerable excipients or auxiliaries.
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* Cited by examiner, † Cited by third party
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EP0420930A1 (en) * 1988-06-15 1991-04-10 LALEZARI, Iraj Method of synthesis and novel compounds for pharmaceutical uses
EP0420930A4 (en) * 1988-06-15 1991-12-04 Iraj Lalezari Method of synthesis and novel compounds for pharmaceutical uses

Also Published As

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US5135949A (en) 1992-08-04
EP0358118B1 (en) 1994-03-16
JPH02117650A (en) 1990-05-02
ATE102918T1 (en) 1994-04-15
DE58907218D1 (en) 1994-04-21
DE3830054A1 (en) 1990-03-15

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